CA2690959A1

CA2690959A1 - 17.beta.-cyano-19-nor-androst-4-ene derivative, its use and medicaments comprising the derivative

Info

Publication number: CA2690959A1
Application number: CA2690959A
Authority: CA
Inventors: Joachim Kuhnke; Jan Huebner; Rolf Bohlmann; Thomas Frenzel; Ulrich Klar; Frederik Menges; Sven Ring; Steffen Borden; Hans-Peter Muhn; Katja Prelle
Original assignee: Bayer Schering Pharma Aktiengesellschaft; Joachim Kuhnke; Jan Huebner; Rolf Bohlmann; Thomas Frenzel; Ulrich Klar; Frederik Menges; Sven Ring; Steffen Borden; Hans-Peter Muhn; Katja Prelle; Bayer Intellectual Property Gmbh
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2007-06-12
Filing date: 2008-06-04
Publication date: 2008-12-18
Also published as: WO2008151746A3; TW200909444A; WO2008151746A2; PA8784401A1; EP2170925B1; AU2008261278A1; MX2009013629A; BRPI0813937A2; US8207150B2; UY31146A1; AR066971A1; KR20100028554A; RU2010100331A; ZA201000187B; ES2397996T3; EP2170925A2; JP2010529153A; DE102007027637A1; PE20090822A1; CN101679478A

Abstract

The 17.beta.-cyano-19-nor-androst-4-ene deriva-tives of the present invention have gestagenic activity. They have the general chemical formula (1), in which Z is selected from the group comprising O, two hydrogen atoms, NOR and NNHSO2R, wherein R is hydrogen or C1-C4 alkyl, R4 is hydro-gen or halogen and in addition either: R6a, R6b together form methylene or 1,2 ethanediyl or R6a is hydrogen and R6b is se-lected from the group comprising hydrogen, methyl and hy-droxymethylene, and R7 is selected from the group compris-ing hydrogen, C1-C4 alkyl, C2-C3 alkenyl and cyclopropyl, or:
R6a is hydrogen and R6b and R7 together form methylene, or are omitted, whereby a double bond is formed between C6 and C7, R9 and R10 are hydrogen, or are omitted, whereby a double bond is formed between C9 and C10, R15 and R16 are hydro-gen or together form methylene, R17 is selected from the group comprising hydrogen, C1-C4 alkyl and aIIyI, at least one of the substituents R4, R6a, R6b, R7, R15, R16 and R17 not being hydro-gen, or R6b and R7 being omitted, whereby a double bond is formed between C6 and C7. The derivatives also comprise the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts of the aforementioned substances.

Description

BSP 53615A WO (engi) 17t3-Cyano-19-nor-androst-4-ene derivative, its use and medicaments comprising the derivative Description:
The invention relates to certain 17R-cyano-19-nor-androst-4-ene derivatives, their use and to medicaments comprising the derivatives and having gestagenic action, for example for the treatment of pre-, peri- and postmenopausal symptoms and of premenstrual symptoms.

From the literature, compounds having gestagenic, antimineralcorticoid, antian-drogenic oder antioestrogenic action based on a steroid structure are known, which are derived, for example, from 19-nor-androst-4-en-3-one or a derivative thereof (the numbering of the steroid structure can be taken, for example, from Fresenius/Gorlitzer 3rd ed. 1991 "Organisch-chemische Nomenklatur" [Organic chemical nomenclature] pp. 60 ff.).

Thus, WO 2006072467 Al describes the compound 6[3,7[i-15[i,16R-dimethylene-3-oxo-17-pregn-4-ene-21,17(3-carbolactone (drospirenone) having gestagenic action, which has been used, for example, in an oral contraceptive and a preparation for the treatment of postmenopausal symptoms. On account of its comparatively low affinity for the gestagen receptor and its comparatively high ovulation-inhibiting dose, drospirenone is contained in the contraceptive, however, in the relatively high daily dose of 3 mg. Drospirenone is moreover distinguished in that, in addition to the gestagenic action, it has aidosterone-antagonistic (antimineralcorticoid) and antiandrogenic action. These two properties make drospirenone very similar in its pharmacological profile to the natural gestagen progesterone which, however, unlike drospirenone is not adequately bioavailable orally. In order to lower the dose to be administered, in WO 2006072467 Al an 18-methyl-1 9-nor-1 7-pregn-4-ene-21,17-carbolactone and pharmaceutical preparations comprising this are further proposed which have a higher gestagenic potency than drospirenone.

BSP 53615A WO (engi) In addition, for example, US-A 3,705,179 discloses steroids which have antiandrogenic activity and are suitable for the treatment of illnesses which are connected with androgens.

In DE 22 26 552 B2, further 17-cyano-19-nor-androst-4-en-3-one compounds are described which show progestomimetic, antiandrogenic and antioestrogenic actions having exogenous character.

The object of the present invention is to make available compounds which have strong binding to the gestagen receptor. Moreover, the compounds should preferably also have an antimineralcorticoid action.

This object was achieved by the novel 17R-nor-cyano-19-androst-4-ene derivatives according to Claim 1, the use of the novel derivatives according to Claim 11, and a medicament comprising at least one novel derivative according to Claim 13.
Advantageous embodiments of the invention are indicated in the subclaims.
The present invention accordingly relates to a 17(3-cyano-19-nor-androst-4-ene derivative having the general chemical formula I

/N
~

R10 ~9 R16 R,5 R~
4 R6a R6b (1) where BSP 53615A WO (engl) Z is selected from the group comprising 0, two hydrogeri.atoms, NOR
and NNHSO2R, in which R is hydrogen or C1-C4-alkyl, R4 is hydrogen or halogen, furthermore either:
R6a, R6b together form methylene or 1,2-ethanediyl or Rsa is hydrogen and Rsb is selected from the group comprising hydrogen, methyl and hydroxymethylene, and R' is selected from the group comprising hydrogen, C1-C4-alkyl, C2-C3-alkenyl and cycfopropyl, or:
R6a is hydrogen and Rsb and R'together form methylene or are omitted with formation of a double bond between C6 and C7 R9, R10 are hydrogen or are omitted with formation of a double bond between C9 and C10 R15 R16 are hydrogen or together form methylene, R17 is selected from the group comprising hydrogen, C1-C4-alkyl and allyi, where at least one of the substituents R4, R6a, Rsb R' R15, R16 and R17 is unequal to hydrogen or R6b and R' are omitted with formation of a double bond between C6 and C7, and its solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.

The numbering of the C ring system of the novel derivative of the general chemical formula I customarily follows the numbering of a steroid ring system, described, for example, in Fresenius, loc. cit. The numbering of the radicals indicated in the claims analogously corresponds to their bonding position to the C ring system of the derivative. For instance, the radical R4 bonds to the C4-position of the novel derivative.

BSP 53615A WO (engl) With respect to the groups defined for Z, the groups NOR and NNHSO2R in each case bond using a double bond via N to the C skeleton of the derivative as in =NOR
and =N-NH-SO2R. OR in NOR and NHSO2R in NNHSO2R can be in the syn or anti position.

Cl-Ca-Alkyl is in each case understood as meaning a straight-chain or branched alkyl radical, namely methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
Particularly preferred are especially the unbranched radicals Methyl, ethyl and n-propyl. Methyl, ethyl and n-propyl are particularly preferred. Alkyl radicals bonded in the 17a position can moreover be perfluorinated , such that R" in this case can moreover be trifluoromethyl, pentafluoroethyl, n-heptafluoropropyl, isoheptafluoropropyl, n-nonafluorobutyl, isononafluorobutyl and tert-nonafluorobutyl.
C2-C3-Alkenyl is preferably to be understood as meaning vinyl or allyl.

Halogen is in each case to be understood as meaning fluorine, chlorine, bromine or iodine.

Isomers are chemical compounds having the same empirical formula, but different chemical structure. Expressly, all possible isomers and isomer mixtures (racemates) are additionally included, the 17(3-cyano position being specified in the novel derivative.

In general, constitutional isomers and stereoisomers are differentiated.
Constitutional isomers have the same empirical formula, but differ in the manner of linkage of their atoms or atomic groups. These include functional isomers, positional isomers, tautomers or valence isomers. In principle, stereoisomers have the same structure (constitution) and thus also the same empirical formula, but differ in the spatial arrangement of the atoms. In general, configurational isomers and conformational isomers are differentiated. Configurational isomers are stereoisomers which can only be converted into one another by bond breakage. These include enantiomers, diastereomers and E/Z (cis/trans) isomers. Enantiomers are stereoisomers which behave as image and mirror image to one another and have no plane of symmetry.
All stereoisomers which are not enantiomers are designated as diastereomers.
E/Z

BSP 53615A WO (engl) (cis/trans) isomers on double bonds are a special case. Conformational isomers are stereoisomers which can be converted into one another by the rotation of single borids. For the delineation of the types of isomerism from one another see also the IUPAC rules, section E (Pure Appi. Chem. 45, 11-30 (1976)).

The novel derivatives having the general chemical formula I also comprise the possible tautomeric forms and include the E or Z isomers or, if a chiral centre is present, also the racemates and enantiomers. Double bond isomers are also to be understood among these.

The novel derivatives can also be present in the form of solvates, in particular of hydrates, the novel compounds accordingly containing polar.solvents, in particular water, as a structural element of the crystal lattice of the novel compounds.
The polar solvent, in particular water, can be present in a stoichiometric or alternatively unstoichiometric ratio. In the case of stoichiometric solvates, hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are also spoken of.

It has been found that the novel compounds or derivatives have a good gestagenic action in vivo. Moreover, some interesting novel compounds act as antagonists for the mineralcorticoid receptor.

Novel derivatives having the aforementioned general chemical formula I are preferred in which Z is selected from the group comprising 0, NOH and NNHSO2H.
Z
is particularly preferably O.

Independently of the selection of Z, novel derivatives having the aforementioned general chemical formula I are furthermore preferred in which the following variants occur alternatively or else at least in some cases together and are selected independently of one another:

R15 and R16 especially preferably together form methylene, where both an a-and a R-methylene group can be bonded in these positions.

R4 is furthermore preferably hydrogen or chlorine.

BSP 53615A WO (engl) R6a and R6b furthermore preferably together form 1,2-ethanediyl or are in each case hydrogen.

R7 is furthermore preferably selected from the group comprising hydrogen and methyl, where the methyl group can be both a- and R-.

R6b and R' furthermore preferably together form methylene, where the methylene group can be both a- and (3-.

R17 is furthermore preferably selected from the group comprising hydrogen and methyl.

The radicals Rsa Rsb R', R15 and R16 can furthermore be both a- and (3-.

The novel 17f3-cyano-19-nor-androst-4-ene derivatives are particularly preferably selected from the group comprising:

" 179-Cyano-613-hydroxymethylene-19-nor-" androst-4-en-3-one H H
H H
/
0 ~H
HO
N 179-Cyano-17a-methyl-19-nor-androst-4-en-3-one H H
H I
/
O
i 17a-Allyl-17f3-cyano-19-nor-androst-4-en-3-one H H

H H
O

= CA 02690959 2009-12-07 BSP 53615A WO (engi) INI 17f3-Cyano-17a-ethyl-19-nor-androst-4-en-3-one H H

H H

N 17R-Cyano-6,6-ethanediyl-19-nor-androst-4-en-3-one ,H
H H

H H

i 17f3-Cyano-6(3, 7f3-methylene-19-nor-androst-4-en-3-one H, H H

H
/ ,=H
O
H
% 179-Cyano-6a, 7a-methylene-19-nor-androst-4-en-3-one H
H H

H H
H
O
H
~' 17f3-Cyano-17a-methyl-6f3-hydroxymethylene-19-nor-and rost-4-en-3-one H H
H H
/
O ,H
HO
gHH, 17f3-Cy ano-15f3, 16f3-methylene-19-nor-androst-4-en-3-one H H -'H

H O

BSP 53615A WO (engi) N 17f3-Cyano-6,6-ethanediyl-l7a-methyl-19-nor-androst-4-en-3-one H H

H
O

N 17f3-Cyano-7a-ethyl-19-nor-androst-4-en-3-one H

H H
H H
O H ''=-..-11 N 1713-Cyano-17a-methyl-6a, 7a-methylene-19-nor-androst-4-en-3-one H H

H H
H
O =
H
N 17f3-Cyano-17a-methyl-6f3, 7f3-methylene-19-n o r-a n d ro st-4-e n-3-o n e H H

H
,,H
O
H
N 17f3-Cyano-7f~-ethyl-19-nor-androst-4-en-3-one H

H H
H H
/
O H
rN 17l3-Cyano-19-nor-androsta-4,6-dien-3-one ~
H
H H

H H

" 17f3-Cyano-17a-methyl-19-nor-androsta-4,6-dien-3-one H H
H H

BSP 53615A WO (engi) ~
N 17(3-Cyano-17a-methyl-15f1,16f3-methylene-19-nor-androst-4-en-3-one H H

O H H H

N 17f3-Cyano-l7a-ethyl-15f3,16R-methylene-l9-nor-a nd rost-4-en-3-one H H H
H H H

~ l 7a, 17a-Bismethyl-17f3-cyano -19-nor-androst-4-en-3-one H H
H H
O / H ~~''~
I % 17f3-Cyano-7a-methyl-19-nor-androst-4-en-3-one ~H
H H

H H
O / H ~~''~
17t3-Cyano-7R-methyl-19-nor-androst-4-en-3-one IH
H H

H H
O H
17f3-Cyano-7a-vinyi-19-nor-androst-4-en-3-one o H O H/ 17f3-Cyano-7f3-vinyl-19-nor-androst-4-en-3-one IH
H H

H H
O H

BSP 53615A WO (engi) N 179-Cyano-7a-cyclopropyl-19-nor-androst-4-en-3-one IH
H H

H
O H '~/

~/ N 17f3-Cyano-7fl-cyclopropyl-19-nor-androst-4-en-3-one ,H
H H

H H
O H

r 1 17f3-Cyano-7a-cyclopropyl-17a-methyl-19-nor-androst-4-en-3-one H H

H HH
O / ~~'v 17f3-Cyano-7f3-cyclopropyl-l7a-methyl-l9-nor-androst-4-en-3-one H H
H HH
O

( 17f1-Cyano-l7a-methyl-7a-vinyl-19-nor-androst-4-en-3-one H H
H H
O H
N 17f3-Cyano-17a-methyl-713-vinyl-19-nor-androst-~ 4-en-3-one ~
,,,, H H

H H
/ -H
-BSP 53615A WO (engl) 17f3-Cyano-159,169-methylene-19-nor-N a nd rosta-4, 6-d i e n-3-o n e IH
H H

H H H
O
N 17f3-Cyano-15f3,16(3-methylene-6f3-hyd roxymethyl-19-nor-androst-4-en-3-one H

H H 'H
H H H
O /
H
OH
N 17a -Ethyl-17f3-cyano-15f3,16(3-methylene-6f3-~~ hydroxymethyl-19-nor-androst-4-en-3-one ,,.~

H H 'H
H H H

O /
=H

OH
% 17R-Cyano-6f3,7f3-15f3,16f3-bismethylene-19-n o r-a n d ro s t-4-e n-3 -o n e ~~H
H
H H

H H H
O
/ õ~H
H

N 17f3-Cyano-6a,7a-15f3,16f3-bismethylene-19-nor-androst-4-en-3-one ~~H

H H
H H H
O H
H

BSP 53615A WO (engl) N 17f3-Cyano-79-cyciopropyl-15f3,169-methylene-19-nor-androst-4-en-3-one ,%H

H H H
H A H
/ -O H

N 179-Cyano-7a-cyclopropyl-15f3,16f3-methylene-19-nor-and rost-4-en-3-one ,%H
H H H
H H H
O H 11, V

N 17f3-Cyano-79-ethyl-159,169-methylene-19-nor-androst-4-en-3-one ,,H

H H H
H H H
O H
N 1 7f3-Cya no-7a-ethyl-159,16 R-methylene-19-nor-androst-4-en-3-one ,%H

H H H
H H
O
H
/ N 17f3-Cyano-7f3-methyl-15f3,16f3-methylene-19-nor-androst-4-en-3-one ,~H
H H ~H
H HH H
~
O

BSP 53615A WO (engl) N 17R-Cyano-7a-methyl-1513,16R-methylene-19-nor-androst-4-en-3-one ,,H
H H H
H HH H
O "''/.
179-Cyano-17a-methyl-15f1,16f3-methylene-19-N nor-androsta-4,6-dien-3-one H H

H H H
O
j 179-Cyano-17a-ethyl-159,169-methylene-19-nor-a nd rosta-4,6-d ien-3-one H H H
H H
O
N Chiral 179-Cyano-159,16R-methylene-7fl-vinyl-19-nor-androst-4-en-3-one ,H

H H H
H H H

O
H
17f3-Cyano-159,16f3-methylene-7a-vinyi-l9-nor-androst-4-en-3-one H H `H
H H
O
H

BSP 53615A WO (engi) N 1713-Cyano-6,6-ethanediyl-15f3,1613-methylene-19-nor-a nd rost-4-en-3-one %H
H H H
H H H
O

N 17f3-Cyano-15a, 16a-methylene-19-nor-androst-~ 4-en-3-one H, H H H
H H H

/ 17f3-Cyano-17a, 7a-dimethyl-159,1613-methylene-19-nor-androst-4-en-3-one H H

H
p / 17f3-Cyano-17a, 7f3-dimethyl-15f3,16f3-,,``` methylene-19-nor-androst-4-en-3-one H H

H H 17f3-Cyano-17a-methyl -7a-ethyl-159,169-methylene-19-nor-a ndrost-4-en-3-one H H
H
O ~~~/
179-Cyano-17a-methyl 713-ethyl-159,16f3-%% methylene-1 9-nor-androst-4-en-3-one H H
H FI

BSP 53615A WO (engi) / 17f3-Cyano-17a-methyl -7a-vinyl-15f~,16(3-methylene-l9-nor-a ndrost-4-en-3-one .~~~~
H H

H H

/ 17f3-Cyano-17a-methyf -7f3-vinyl-15f1,16(3-methylene-l9-nor-androst-4-en-3-one ~~~~~

H H
H

/ 17f3-Cyano-l7a-methyl-7a-cycfopropyl-15f3,16f3-methylene-l9-nor-androst-4-en-3-one H H

H H

0 179-Cyano-17a-methyl-79-cyclopropyl-159,16f1-methylene-19-nor-androst-4-en-3-one H H

H

/ 17f3-Cyano-l7a-methyl-6f3-hydroxymethyl-15f3,16f3-methylene-l9-nor-androst-4-en-3-one ~~~~~

H H
y O C

OH
/ 179-Cyano-1 7a-methyl-6,6-ethylene-159,169-methylene-1 9-nor-androst-4-en-3-one H H
H
O

BSP 53615A WO (engi) ~ 17f3-Cyano-17a-methyl-6f3,7f3-methylene-15f3,16f3-methylene-19-nor-androst-4-en-3-one ~~~~~

H H
H li O
17f3-Cyano-l7a-methyl-6a,7a-methylene-~~ 15f3,16(3-methylene-19-nor-androst-4-en-3-one fol H H
H

''4 17f3-Cyano-17a-ethyl-7a-methy!-159,16(3-methylene-19-nor-androst-4-en-3-one H H

H

3-Cyano-17a-ethyl-7f3-methyl 15f3,16f3-17f methylene-19-nor-androst-4-en-3-one rov `~
H H

H

179-Cyano-17a,7a-diethyl-15(3,16f3-methylene-19-nor-androst-4-en-3-one H H

H
p '~~~/
17f3-Cyano-17a,79-diethyl-15f3,169-methylene-19-nor-androst-4-en-3-one =``~~
H H
H

BSP 53615A WO (engi) 17f3-Cyano-17a-ethyl -7a-vinyl-15f3,169-methylene-19-nor-androst-4-en-3-one .=`~~
H H
H Hr O
17R-Cyano-17a-ethyl-79-vinyl-159,169-methylene-l9-nor-androst-4-en-3-one .=`~~
H H
O Ao H

179-Cyano-l7a-ethyl-7a-cyclopropyl-159,16f3-methylene-19-nor-androst-4-en-3-one .=`~~'~.

H H
H H

179-Cyano-17a-ethyl-79-cyclopropyl-15f3,16f3-=`N methylene-19-nor-androst-4-en-3-one H H

H
O Alo 17f3-Cyano-l7a-ethyl-6,6-ethy{ene-159,16(3-methylene-19-nor-androst-4-en-3-one .=`~~
H H
H H
~
.~
~.

179-Cyano-17a-ethyl-6f3,7f3-methylene-,4N 15f3,169-methylene-19-nor-androst-4-en-3-one H H

H

BSP 53615A WO (engl) 179-Cyano-17a-ethyl-6a,7a-methylene-15R,169-methylene-19-nor-androst-4-en-3-one H H

H
O =

The 15a,16a- and the 15(3,16(3-methylene derivatives in the above list are very particularly preferred.

On account of their gestagenic activity, the novel compounds having the general chemical formula 1 can be used alone or in combination with oestrogens in medicaments for contraception.

The derivatives according to the invention are therefore suitable in particular for the production of a medicament for oral contraception and for the treatment of pre-, peri-and postmenopausal symptoms, including use in preparations for hormone replacement therapy (HRT).

Because of their favourable profile of action, the derivatives according to the invention are particularly highly suitable for the treatment of premenstrual symptoms, such as headaches, depressive disgruntlements, water retention and mastodynia.
The use of the derivatives according to the invention for the production of a medicament having gestagenic and antimineralcorticoid action is particularly preferred.

Treatment with the derivatives according to the invention preferably takes place in humans, but can also be carried out on related mammalian species, such as, for example, on dog and cats.

For the use of the derivatives according to the invention as medicaments, these are combined with at least one suitable pharmaceutically harmless additive, for example vehicle. The additive is suitable, for example, for parenteral, preferably oral, administration. It is a matter here of pharmaceutically suitable organic or inorganic BSP 53615A WO (engl) inert additive materials, such as, for example, water, gelatine, gum arabicum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc.
The medicaments can be present in solid form, for example as tablets, coated tablets, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions. Optionally, they moreover contain excipients, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. For parenteral administration, oily solutions, such as, for example, solutions in sesame oil, castor oil and cottonseed oil, are in particular suitable. To increase the solubility, solubilizers, such as, for example, benzyl benzoate or benzyl alcohol, can be added. It is also possible to incorporate the derivatives according to the invention into a transdermal system and thus to administer it transdermally. For oral administration, tablets, coated tablets, capsules, pills, suspensions or solutions are in particular suitable.

The dose of the derivatives according to the invention in contraception preparations should be 0.01 to 10 mg per day. The daily dose in the case of the treatment of premenstrual symptoms is approximately 0.1 to 20 mg. The gestagenic derivatives according to the invention are preferably administered orally in contraception preparations and in the medicaments for the treatment of premenstrual symptoms.
The daily dose is preferably administered as a single dose.

The gestagenic and oestrogenic active substance components are preferably administered together orally in contraception preparations. The daily dose is preferably administered as a single dose.

Possible oestrogens are synthetic oestrogens, preferably ethinylestradiol, but also mestranol.

The oestrogen is administered in a daily amount which corresponds to that of 0.01 to 0.04 mg of ethinylestradiol.

Oestrogens, of course, are primarily used as oestrogens in the medicaments for the treatment of pre-, peri- and postmenopausal symptoms and for hormone replacement BSP 53615A WO (engi) therapy, especially oestradiol or its esters, for example oestradiol valerate, or alternatively conjugated oestrogens (CEEs = Conjugated Equine Estrogens).

If the preparation of the starting compounds is not described here, these are known to the person skilled in the art or can be prepared analogously to known compounds or processes described here. The isomer mixtures can be separated into the enantiomers, E/Z isomers or epimers by customary methods, such as, for example, crystallization, chromatography or salt formation.

The derivatives according to the invention having the general chemical formula I are prepared as described below.

Suitable starting materials for the 173-cyano-19 nor-androst-4-en-3-one derivatives described here are various steroidal starting materials, such as, for example, 19-nor-and rost-4-en e-3,1 7-dione, or alternatively the partially reduced analogues.

Microbiologically, for example, 15a-hydroxy-19-nor-androst-4-ene-3,17-dione is accessible, which opens up access to 15f3,16R-methylenated 17-cyanosteroids, for this see examples in the experimental section. 15a,16a-Methylenated precursors which are suitable for the synthesis of the corresponding 17-cyanosteroids are likewise known, e.g. 1713-hydroxy-15a,16a-methylene-19-nor-androst-4-en-3-one in DE-A 22 07 421 (1973). Access to 17(3-cyano-19-nor-androst-4-en-3-one is described in DE-A 22 26 552.

It is obvious to the person skilled in the art that in the descriptions of the synthetic transformations it is always provided for other functional groups optionally present on the steroid ring system to be protected in suitable form.

The introduction of a nitrile into position 17 (C17) of the steroid ring system can be carried out in a variety of ways. Both single-stage processes and multistage variants are possible here. Methods are preferred here which finally mean the replacement of an oxygen function by cyanide. Many possible process variants are described in Science of Synthesis Houben-Weyl Methods of Molecular Transformations Category 3 Volume 19 pp. 197-213 (2004 Georg Thieme Verlag Stuttgart, New York) and in BSP 53615A WO (engl) Houben-Weyl Methoden der organischen Chemie [Houben-Weyl Methods of organic chemistry] Volume E5 Part 2 pp. 1318-1527 (1985 Georg Thieme Veriag Stuttgart, New York).

A single-stage process which suggests itself is, for example, the direct reductive replacement of a carbonyl oxygen atom by a cyano group. For this, a 17-ketosteroid is reacted with tosylmethyl isocyanide in suitable solvents, such as, for example, dimethoxyethane, dimethyl sulphoxide, ethers, alcohols or alternatively their mixtures, using suitable bases, such as, for example, alkali metal alkoxides, alkali metal hydrides, potassium hexamethyldisilazide, or alternatively alkali metal amides, such as, for example, lithium diisopropylamide, in a temperature range from 0 C to 100 C. 17-Epimer mixtures which may be formed can be separated by chromatography, fractional crystallization or using a combination of these methods.
The SN2-type replacement of a suitable leaving group in position 17, such as, for example, of a halide (preferably iodine or bromine), or alternatively of a sulphonic acid ester of a 17-alcohol, by cyanide is also possible. Cyanide sources used are preferably inorganic cyanides, such as lithium cyanide, sodium cyanide and potassium cyanide.

The following may be mentioned as examples of multistage variants of nitrile introduction: a 17-ketone is converted by means of a Wittig olefination to the corresponding 17-exomethylene compound, which after hydroboration and oxidation to the aidehyde can be reacted to give the corresponding 17-carbaidehyde oxime.
Dehydration of the oxime then leads to the 17-nitrile.

The introduction of the nitrile can be carried out both at the beginning of a synthesis sequence and also at any desired later point in time, provided that further functional groups which may be present are protected in a suitable manner.

The 17-cyano compounds can be optionally alkylated, which leads to stereochemically homogeneous 17(3-cyano-17a-substituted derivatives. For this, the 17-cyanosteroid is deprotonated in a suitable solvent, such as, for example, ethers, for example tetrahydrofuran. Various bases can be used here, for example an alkali BSP 53615A WO (engi) metal amide, such as lithium diisopropylamide. After addition of an alkylating agent, such as, for example, of an alkyl or alkenyl halide, and work-up, the 1713-cyano-17a-substituted derivatives are then obtained.

By way of example, the further synthetic procedure may be illustrated with the aid of the following synthesis scheme, the compound 2 (DE-A 22 26 552 (1972)) already described being mentioned as a starting material:

Scheme I
N
O
Z
N N N
-a ---R~, N \ O
9 $
R

N /N N
O / O O
oH 11 12 OSOZR

The introduction of a 6,7-double bond is carried out by means of bromination of the 3,5-dienol ether 5 and subsequent elimination of hydrogen bromide (see, for example, J. Fried, J.A. Edwards, Organic Reactions in Steroid Chemistry, von Nostrand Reinhold Company 1972, pp. 265-374).

The introduction of a substituent R4 can be achieved, for example, starting from a compound of the formula 2, by epoxidation of the 4,5-double bond with hydrogen BSP 53615A WO (engl) peroxide under alkaline conditions and reaction of the resulting epoxides in a suitable solvent with acids having the general chemical formula H-R4, where R4 can be a halogen atom or a pseudohalogen, or by reacting with catalytic amounts of mineral acid and optionally reacting the 4-bromo compounds obtained having the general chemical formula 1(where R4 = bromine) with methyl 2,2-difluoro-2-(fluorosulphonyl)-acetate in dimethylformamide in the presence of copper(I) iodide.

The dienol ether bromination of compound 5 can be carried out, for example, analogously to the procedure of Steroids 1, 233 (1963). The elimination of hydrogen bromide is possible by heating the 6-bromo compound with basic reagents, such as, for example, LiBr or Li2CO3, in aprotic solvents, such as dimethylformamide, at temperatures from 50 C to 120 C or else by heating the 6-bromo compounds in a solvent, such as codlidirie or lutidine, to give compound 6.

Compound 7 is converted by methenylation of the 6,7-double bond according to known processes, for example using dimethylsulphoxonium methylide (see, for example, DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US-A 4,291,029; J.
Am. Chem. Soc. 84, 867 (1962)) to a compound 8, a mixture of the a- and R-isomers being obtained, which can be separated into the individual isomers, for example, by chromatography.

Compounds of the type 7 can be obtained as described in the examples or analogously to these procedures using reagents analogous to those described there.
The synthesis of the spirocyclic compound 12 starts from 2, which is first converted to a 3-amino-3,5-diene derivative 9. By reaction with formalin in alcoholic solution, the 6-hydroxymethylene derivative 10 is obtained. After conversion of the hydroxyl group to a leaving group, such as, for example, a mesylate, tosylate (compound 11) or alternatively benzoate, compound 13 can be prepared by reaction with trimethylsulphoxonium iodide using bases, such as, for example, alkali metal hydroxides or alkali metal alkoxides, in suitable solvents, such as, for example, dimethyl sulphoxide.

BSP 53615A WO (engl) For the introduction of a 6-methylene group, compound 10 can be dehydrated using, for example, hydrochloric acid in dioxane/water. 6-Methylene can also be produced from 11 (see DE-A 34 02 3291, EP-A 0 150 157, US-A 4,584,288; J. Med. Chem.
34, 2464 (1991)).

A further possibility for the preparation of 6-methylene compounds consists in the direct reaction of the 4(5) unsaturated 3-ketones, such as compound 2, with acetals of formaldehyde in the presence of sodium acetate using, for example, phosphorus oxychloride or phosphorus pentachloride in suitable solvents, such as chloroform (see, for example,. K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982)).

The 6-methylene compounds carr be used for the preparation of compounds having the general formula 1, in which R6a is equal to methyl and R6b and R7 are omitted with formation of a double bond between C6 and C7.

For this, for example, a process described in Tetrahedron 21, 1619 (1965) can be used, in which an isomerization of the double bond is achieved by warming the methylene compounds in ethanol with 5% palladium-carbon catalyst, which was pretreated either with hydrogen or by warming with a small amount of cyclohexene.
The isomerization can also be carried out using a catalyst which was not pretreated, if a small amount of cyclohexene was added to the reaction mixture. The occurrence of small amounts of hydrogenated products can be prevented by addition of an excess of sodium acetate.

The 6-methyl-4,6-dien-3-one derivatives, however, can also be prepared directly (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983)).
Compounds in which R6b is an a-methyl function can be prepared from the 6-methylene compounds by hydrogenation under suitable conditions. The best results (selective hydrogenation of the exo-methylene function) are achieved by transfer hydrogenation (J. Chem. Soc. 3578 (1954)). If the 6-methylene derivatives are heated in a suitable solvent, such as, for example, ethanol, in the presence of a hydride donor, such as, for example, cyclohexene, 6a-methyl derivatives are BSP 53615A WO (engl) obtained in very good yields. Small amounts of 6R-methyl compound can be isomerized by acid (Tetrahedron 1619 (1965)).

The selective preparation of 6[3-methyl compounds is also possible. For this, the 4-en-3-ones, such as, for example, compound 2, are reacted, for example, with ethylene glycol or trimethyl orthoformate in dichloromethane in the presence of catalytic amounts of an acid, e.g. p-toluenesulphonic acid, to give the corresponding 3-ketals. During this ketalization, the double bond in position 5(C5) isomerizes. A
selective epoxidation of this 5-double bond is possible, for example, by use of organic peracids, e.g. of m-chloroperbenzoic acid, in suitable solvents, such as dichloromethane. Alternatively to this, the epoxidation can also be carried out using hydrogen peroxide in the presence of, for example, hexachloroacetone or 3-nitrotrifluoroacetophenone. The 5,6a-epoxides can then be opened axially using appropriate alkylmagnesium halides or alkyllithium compounds. 5a-Hydroxy-6[3-alkyl compounds are thus obtained. The cleavage of the 3-keto protective group can be carried out with obtainment of the 5a-hydroxyl function by treating under mild acidic conditions (acetic acid or 4 N hydrochloric acid at 0 C). Basic elimination of the 5a-hydroxyl function using, for example, diluted aqueous sodium hydroxide solution affords the 3-keto-4-ene compounds having a R-6-alkyl group. Alternatively to this, ketal cleavage under more drastic conditions (aqueous hydrochloric acid or another strong acid) affords the corresponding 6a-alkyl compounds.

The compounds having the general chemical formula 1 obtained, in which Z is an oxygen atom, can be converted to their corresponding oximes (general chemical formula 1 with Z denoting NOH, where the hydroxyl group can be syn- or anti-) by reaction with hydroxylamine hydrochloride in the presence of a tertiary amine at temperatures between -20 and +40 C. Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N,N-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), pyridine being preferred. This applies analogously as is described in WO-A

for the preparation of corresponding 3-oxyimino derivatives of drospirenone.

The removal of the 3-oxo group for the preparation of a final product having the general chemical formula I with Z denoting two hydrogen atoms can be carried out, BSP 53615A WO (engi) for example, by reductive cleavage of a thioketal of the 3-keto compound according to the procedure indicated in DE-A 28 05 490.

The following examples serve for the more detailed illustration of the invention:
The compounds according to the invention are surprisingly distinguished by strong gestagenic activity and are strongly active in the maintenance of pregnancy test on the rat after subcutaneous administration.

Carrying out the maintenance of pregnancy test on the rat:

In pregnant rats, the removal of the corpora lutea or oophorectomy induces an abortion. By means of the exogenous administration of progestins (gestagens) in combination with a suitable dose of an oestrogen, the maintenance of pregnancy is possible. The maintenance of pregnancy test on ovarectomized rats serves for the determination of the peripheral gestagenic activity of a compound.

Rats were paired overnight during proestrus. Pairing was checked on the morning of the following day by the appraisal of a vaginal smear. The presence of the sperm was evaluated here as day 1 of a commencing pregnancy. On day 8 of the pregnancy, the animals were ovarectomized under ether anaesthesia. The treatment with test compound and exogenous oestrogen (oestrone, 5 pg/kg/day) was carried out subcutaneously once daily from day 8 to day 15 or day 21 of the pregnancy.
The first administration on day 8 was carried out two hours before oophorectomy.
Intact control animals were given exclusively vehicle.

Evaluation:
At the end of the experiment (day 15 or day 21), the animals were sacrificed under a CO2 atmosphere, and live foetuses (foetuses having a beating heart) and implantation sites (early resorptions and dead foetuses including autolysis and atrophic placentas) were counted in both uterine horns. On day 22, it was moreover possible to examine foetuses for malformations. In uteri without foetuses or implantation sites, the number of nidation sites was determined by staining with 10%

BSP 53615A WO (engl) strength ammonium sulphide solution. The maintenance of pregnancy rate was calculated as the quotient of the number of living foetuses and the total number of nidation sites (both resorbed and dead foetuses and nidation sites). For certain test substances, the pregnancy-maintaining doses (ED50) indicated in Table 1 were determined. For drospirenone, this value is 3.5 mg/kg/day.

The derivatives according to the invention having the general chemical formula have a very strong gestagenic activity. It was moreover found that the derivatives according to the invention show antimineralcorticoid action in vitro. They should therefore have in vivo potassium-retaining, natriuretic (antimeralcorticoid) action.
These properties were determined using the test described below:

For the culturing of the cells used for the assay, the culture medium used was DMEM
(Dulbecco's Modified Eagle Medium: 4500 mg/mI of glucose; PAA, #E15-009) with 10% FCS (Biochrom, S0115, batch #615B), 4 mM L-glutamine, 1%
penicillin/streptomycin, 1 mg/mI of G418 and 0.5 pg/mI of puromycin.

Reporter cell lines were grown in a density of 4 x 104 cells per hollow in white, nontransparent tissue culture plates in each case having 96 hollows (PerkinElmer, #P12-106-017) and kept in 6 % DCC-FCS (activated carbon-treated serum, for the removal of interfering components contained in the serum). The compounds to be investigated were added eight days later, and the cells were incubated with the compounds for 16 hours. The experiments were carried out in triplicate. At the end of the incubation, the effector-containing medium was removed and replaced by lysis buffer. After luciferase assay substrate (promega, #E1501) had been added, the plates containing the 96 hollows were then introduced into a microplate luminometer (Pherastar, BMG labtech), and the luminescence was measured. The IC50 values were evaluated using software for the calculation of dose-activity relationships.
Experimental results are presented in Table 1:

BSP 53615A WO (engl) Table 1 Compound MR Antagonism IC50 MR Antagonism PR in vivo ED50 [nMI activity [% of the [mg/kg/d s.c.]
maximum effect) 179-Cyano-15a,16a-methylene-19- 16.0 93.01 0.8 nor-androst-4-en-3-one 17(3-Cyano-17a-methyf-15(3,169- 29.0 96.00 0.8 methyl ene-19-nor-androst-4-en-3-on e 7a,17a-Bismethyl-17f3-cyano-19-nor- 31.0 96.20 1.0 androst-4-en-3-one 179-Cyano-159, 169-methylene-l9- 4.5 95.57 0.84 nor-androst-4-en-3-one 17R-Cyano-17a-ethyl-15(3,169- 440 106.4 1.9 meth ylene-19-nor-a ndrost-4-en-3-on e 17(3-Cyano-7a-methyl-19-nor- 8.2 108.02 0.33 androst-4-en-3-one 17(3-Cyano-15f3,16R-methylene-19- 15 108.51 3.3 nor-a ndrosta-4,6-d ien-3-on e 17f3-Cyano-17a-methyl-15f3,16f5- 190 114 2.1 methylen e-19-nor-a nd rosta-4,6-dien-3-one 179-Cyano-7a-methyl-159,169- 8.3 108.4 0.11 methylene-1 9-nor-androst-4-en-3-one 179-Cyano-7a-methyl-159,169- 10.3 110 2.9 methylen e-19-nor-a ndrost-4-en-3-one 17f3-Cyano-17a-ethyl-6a,7a- 90.17 160 0.22 methylene-1513,169-methylen-l9-n or-androst-4-en-3-one The following examples for the synthesis of preferred compounds serve for the further illustration of the invention. The new intermediates disclosed in the individual BSP 53615A WO (engf) synthesis examples are, just like the 17f3-cyano-19-nor-androst-4-ene derivatives according to the invention, essential to the invention.

Many of the reactions described below lead to epimer mixtures. Usually, the chromatographic separation of these mixtures via preparative HPLC is carried out under the following conditions: separations were carried out on a chiral normal phase, the stationary phase usually used being Chiralpak AD-H 5p. Customarily, elution was carried out using a mixture of hexane and ethanol. In some cases, however, other eluent mixtures, such as, for example, mixtures of methanol and ethanol, were used:

BSP 53615A WO (engl) Example 1 17 (3-Cya n o-15R,16(3-m ethyle ne-19-n or-a n d rost-4-en-3-one 1a.
15a-Acetoxy-19-nor-a n d rost-4-ene-3,17-d ione 95 g of 15a-hydroxy-19-nor-androstenedione (described in DE-A 24 56 068; 1976) were dissolved in 332 ml of pyridine. After addition of 166 ml of acetic anhydride, the solution was stirred at room temperature for three hours. The reaction mixture was then poured into a mixture consisting of 10 I of ice water, 109 mi of conc.
sulphuric acid and 16 mi of methanol. After stirring overnight, the precipitate was filtered off with suction and the filter residue was washed with 3 litres of water. 15a-Acetoxy-19-nor-androst-4-ene-3,17-dione was obtained, which was reacted further without purification.

1 b.
15a-Acetoxy-3-methoxy-19-nor-androsta-3, 5-dien-17-one 90.6 g of the compound described in Example 1a were suspended in 955 mi of 2,2-dimethoxypropane and treated with 10.3 g of pyridinium tosylate. After heating the reaction mixture to 100 C for 6.5 hours, it was stirred overnight at RT. After addition of 13.8 ml of pyridine, it was partially concentrated under reduced pressure on a rotary evaporator and the remaining flask contents were treated with 550 ml of methanol. After stirring at room temperature for one and a half hours, the mixture was cooled to 0 C, filtered off with suction and the filter cake was dried.
15a-Acetoxy-3-methoxy-1 9-nor-androsta-3,5-dien-1 7-one was thus obtained.

'H-NMR (d6-DMSO): 0.87(s,3H,18-CH3), 1.98(s,3H,CH3-CO-), 3.46(s,3H,3-O-CH3), 5.10(m,1H,H-15), 5.18(s,1H,H-4), 5.21(m,1H,H-6) 1 c.
159,16R-Methylene-3-methoxy-l9-nor-androsta-3,5-dien-17-one 26.03 g of trimethylsuiphoxonium iodide and 8.3 g of powdered sodium hydroxide were stirred in 344 ml dimethyl sulphoxide at a bath temperature of 50 C for BSP 53615A WO (engi) minutes. The solution thus obtained was added dropwise in the course of 5 minutes to a suspension of 33.4 g of the compound described in Example 1 b in 110 ml of dimethyl sulphoxide. After 20 minutes, the batch was transferred to a beaker and 500 ml of water were slowly added dropwise with stirring. After the mixture had been stirred for 20 minutes, it was filtered off with suction through a frit and the filter cake was dried. 1513,16f3-Methylene-3-methoxy-19-nor-androsta-3,5-dien-l7-one was obtained.

1H-NMR (d6-DMSO): 0.91(s,3H,18-CH3), 3.51(s,3H,3-O-CH3), 5.26(s,1H,H-4), 5.33( m,1 H, H-6) 1d.
17-Cyano-1511,16R-methylene-3-methoxy-l9-nor-androsta-3,5-diene 2.5 g of the compound described in Example 1 c were initially introduced into a mixture of 40 mi of 1,2-dimethoxyethane and 25 ml of tertiary-butanol. After introduction of 4.7 g of potassium tertiary butoxide, 2.77 g of tosylmethyl isocyanide (TOSMIC) were added, and the mixture was stirred for 90 minutes. The batch was added to the tenfold amount of ice water, common salt was added to saturation and the mixture was filtered. The filter cake was taken up in ethyl acetate, the solution was washed with water and common salt solution, dried over sodium sulphate and filtered and the filtrate was concentrated. A mixture of 17a-cyano- and 17f3-cyano-15f3,16R-methylene-3-methoxy-19-nor-androsta-3,5-diene was obtained, which was reacted further without purification.

1 e.
17(3-Cyano-15B,16R-methyle ne-19-nor-androst-4-en-3-one 2.8 g of the crude isomer mixture described in Example 1d were stirred for 3 hours in a mixture of 100 ml of acetone and 10 ml of 1 normal HCI. After neutralization of the reaction mixture with saturated sodium hydrogencarbonate solution, it was extracted with ethyl acetate and the organic phase was subsequently washed with water and saturated common salt solution. After drying over sodium sulphate, it was filtered, the filtrate was concentrated and the residue was first chromatographed on silica gel with BSP 53615A WO (engl) a gradient of the solvents n-hexane and ethyl acetate. The product-containing fractions were then chromatographed again on silica gel using a mixture of n-hexane and ethyl acetate.

The fractions mainly containing the desired product were combined, concentrated and recrystallized from a mixture of diisopropyl ether and acetone. 17R-Cyano-15f3,16f3-methylene-19-nor-androst-4-en-3-one was obtained as a crystallizate.
The mother liquor and the residual product-containing fractions from the chromatography afforded, after concentration, a mixture of 17a-cyano- and 17f3-cyano-1513,16f1-methylene-19-nor-androst-4-en-3-on e.

1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8=
0.46(m,1H), 0.90(m,1H); 1.04(m,1H), 1.10(s,3H,18-CH3 ), 1.67(m,1H), 1.86(m,2H), 2.11(m,2H), 2.55(m,1H), 2.77(d broad, 1 H,J=4.4Hz, 1 7-H), 5.86(s,1H, H-4) Example 2 179-Cyano-15(3,16f3-methylene-19-nor-androsta-4,6-dien-3-one 2a.
17(3-Cyano-15(3,16(3-methylene 3-methoxy-19-nor-androsta-3,5-diene 9g of 17f3-cyano-159,16(3-methylene-19-nor-androst-4-en-3-one (see Example 1 e), dissolved in 92 ml of methanol, were treated with 83 ml of methyl orthoformate. After addition of 53 mg of p-toluenesulphonic acid, the mixture was stirred at 15 C.
A
precipitate was formed. After addition of 0.8 mi of pyridine at 0 C, the mixture was cooled to -10 C and stirred for 30 minutes. After concentration under reduced pressure, 17f3-cyano-159,16f3-methylene 3-methoxy-1 9-nor-androsta-3,5-diene was obtained, which was reacted further without purification.

2b.
17t3-Cyano-1513,169-methylene-l9-nor-androsta-4,6-dien-3-one A suspension of 3.4 g of 17R-cyano-15f1,16f3-methylene 3-methoxy-19-nor-androsta-3,5-diene in 100 ml of 1-methyl-2-pyrrolidone was treated in succession at 0 C
with 4 ml of a 10% strength sodium acetate solution and at this temperature with 1.6 g of BSP 53615A WO (engl) 1,3-dibromo-5,5-dimethylhydantoin in portions, stirred for 0.5 hour at 0 C
(ice bath), treated with 1.5 g of lithium bromide and 1.3 g lithium carbonate, and stirred at a bath temperature of 100 C for 3.5 hours. Subsequently, the mixture was stirred in ice water/common salt, and the precipitate was filtered off. 179-Cyano-15f3,16R-methylene-19-nor-androsta-4,6-dien-3-one was obtained.

'H-NMR (300 MHz, CDC13 TMS as internal standard, selected signals): 8=
0.54(m,1 H, cyclopropyl) 1.10 (m,1 H, cyclopropyl), 1.12(s,3H, 18-CH3 ), 2.80(d,1 H,J=4.4, H-17), 5.81(s,1 H, H-4), 6.27(m,1 H, H-6), 6.41(m,1 H,H-7) Example 3 17R-Cyano-1513,16t3-methylene-7a-methyl-19-nor-androst-4-en-3-one and 1713-cyano-15(3,169-methylene-7l3-methyl-19-nor-androst-4-en-3-one 67 mg of copper(I) chloride were added at room temperature to a solution of 1.0 g of 17R-cyano-15f3,1611-methylene-19-nor-androsta-4,6-dien-3-one in 50 ml of tetrahydrofuran and the mixture was stirred for 10 minutes before being cooled to -15 C, treated with 450 mg of aluminium chloride, stirred at this temperature for 30 minutes, treated dropwise with 4.5 ml of methylmagnesium bromide solution (3 M
in tetrahydrofuran), and stirred for one hour at -15 C. For work-up, the reaction mixture was treated at -15 C with 30 ml of 2 M hydrochloric acid, stirred for 0.5 hours at room temperature, added to water, extracted three times with ethyl acetate, dried over sodium sulphate, concentrated in vacuo, and chromatographed on silica gel using hexane/ethyl acetate. 17f3-Cyano-7a-methyl-18a-homo-19-nor-androst-4-en-one was obtained as fraction I and 17R-cyano-15f3,16R-methylene-79-methyl-19-nor-androst-4-en-3-one was obtained as fraction II.
1711-Cyano-15f3,169-methylene-7a-methyl-19-nor-androst-4-en-3-one:
1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): S= 0.45 (m,1H,cyclopropyl)0.88(d,3H,J=6.97, 7-CH3), 1.03(m,1H,cyclopropyl) 1.10(s,3H, 18-CH3 ), 5.86(s,IH, H-4) 179-Cyano-1513,1611-methylene-7f3-methyl-19-nor-androst-4-en-3-one:

BSP 53615A WO (engi) 'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): &= 0.53 (m,1H,cyclopropyl)1.01 (m,1H,cyclopropyl) 1.10(s,3H, 18-CH3), 1.21 (d,3H,J=6.22, 7-CH3), 5.83(s,1H, H-4) Example 4 1713-Cyano-7a-ethyl-15R,169-methylene-19-nor-androst-4-en-3-one and 17R-+cya no-7t3-ethyl-15t3,1613-methylene-19-nor-androst-4-en-3-one According to the method of Example 3 using ethylmagnesium bromide in ether instead of methylmagnesium bromide, after chromatography 17t3-cyano-7a-ethyl-15(3,16(3-methylene-19-nor-androst-4-en-3-one was obtained as fraction I and 17(1-cyano-79-ethyl-1513,16(3-methylene-19-nor-androst-4-en-3-one was obtained as fraction II.

17(3-Cya no-7a-ethyl-15(3,16f3-m ethytene-19-nor-and rost-4-en-3-on e:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): S= 0.46 (m, 1 H,cyclopropyl) 0.92 (m,3H, 7-CH3-CH2), 1.03(m,1H,cyclopropyl)1.10(s,3H, CH3 ), 5.87(s,1 H, H-4) 17(3-Cyano-7R-ethyl-15R,16R-methylene-19-nor-androst-4-en-3-one:
1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): S= 0.54 (m,1H,cyclopropyl) 0.95 (m,3H, 7-CH3-CH2), 1.02(m,1H,cyclopropyl) 1.1 1(s,3H, CH3 ), 5.84(s,1 H, H-4) Example 5 17R-Cyano-7a-vinyl-15R,16t3-methylene-19-nor-androst-4-en-3-one and 17(3-cya-no-79-vinyi-15(3,16R-methylene-19-nor-androst-4-en-3-one According to the method of Example 3 using vinylmagnesium bromide instead of methylmagnesium bromide, after chromatography 179-cyano-7a-vinyl-15f3,16(3-methylene-19-nor-androst-4-en-3-one was obtained as fraction I and 179-cyano-7f3-vinyl-159,16f3-methylene-1 9-nor-androst-4-en-3-one was obtained as fraction II.
17f3-Cyano-7a-vinyl-1513 169-methylene-19-nor-androst-4-en-3-one:

BSP 53615A WO (engl) 1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8= 0.51 (m,1H,cyclopropyl), 1.08(m,1H,cyclopropyl) 1.14(s,3H, 18-CH3 ),5.22(m,2H, CH2=CH), 5.88 (m, 1 H,CH2=CH) 5.92(s,1H, H-4) BSP 53615A WO (engl) 1 7R-Cya no-7(3-vinyl-15R,16t3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 6= 0.42 (m,1H,cyclopropyl), 0.95(m,1H,cyclopropyl) 1.10(s,3H, 18-CH3 ),5.05(m,2H, CH2=CH), 5.86(s,1 H, H-4), 5.88 (m,1 H,CH2=CH) Example 6 17t3-Cyano-7a-cyctopropyl-15(3,16(i-methylene-19-nor-androst-4-en-3-one and 179-cyano-713-cyclopropyl-159,16f3-methylene-l9-nor-androst-4-en-3-one According to the method of Example 3 using cyclopropylmagnesium bromide instead of methylmagnesium bromide, after chromatography 17R-cyano-7a-cyclopropyl-1511,16(3-methylene-19-nor-androst-4-en-3-one was obtained as fraction I and -17f3-cyano-7f3-cyclopropyi-15fs,16f3-methylene-19-nor-androst-4-en-3-one was obtained as fraction II.

17f3-Cyano-7a-cyclopropyl-15f3,16f3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 6 =-0.05(m,1H,cyclopropyl), 0.26(m,1H,cyclopropyl), 0.47(m,3H, cyclopropyl), 1.08(s,3H, 18-CH3 ), 5.90(s,1 H, H-4) 1 7 f3-C ya n o-7 f3-cycl o p ropyl -15 11,16 f3-m eth yl e n e-19-n o r-a n d rost-4-e n-3-o n e:
'H-NMR (300 MHz, CDC13 TMS as internal standard, selected signals): 8=
0.29(m,2H,cyclopropyl), 0.47(m, 1 H,cyclopropyl), 0.60(m,2H, cyclopropyl), 0.78(m, 1 H, cyclopropyl), 0.97(m,3H, cyclopropyl), 1.12(s,3H, 18-CH3), 5.81(s,1H, H-4) Example 7 17f3-Cyano-6(3-hydroxymethyl-15(3,16f3-methylene-l9-nor-androst-4-en-3-one 3 g of 17(3-cyano-150,16P-methylene-19-nor-androst-4-en-3-one (see Example 1 e) were taken up in 16 ml of methanol, treated with 1.6 ml of pyrrolidine and warmed to reflux for 1 h. After cooling, the precipitate was filtered off with suction, washed with a little cold methanol and sucked dry. The crystallizate was dissolved in 30 ml of benzene and 60 ml of ethanol, and 3.1 ml of 30 % strength formaldehyde solution were added. After stirring at room temperature for 2h, the mixture was concentrated BSP 53615A WO (engl) to dryness and chromatographed on silica gel. 17f3-Cyano-6(3-hydroxymethyl-15(3,16(3-methylene-19-nor-androst-4-en-3-one was obtained.

1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8=
1.09(s,3H, 18-CH3), 0.43-1.06(m,2H,cyclopropyl), 3.74(m,2H,CH2OH) 5.94(s, 1 H, H-4) Example 8 179-Cyano-6,6-ethylene-15R,169-methylene-l9-nor-androst-4-en-3-one 8a.
17t3-Cyano-15(3,16(3-methylene -69-tosyloxymethyl -19-nor-androst-4-en-3-one 2.93 g of para-toluenesulphonyl chloride were added in one portion to a solution of 1.74 g of 17f3-cyano-6(3-hydroxymethyl-15f3,16f3-methylene-19-nor-androst-4-en-one in 20 ml of pyridine and stirred for 6 hours at room temperature. After this, the reaction mixture was poured into ice-cold 1 N HCI, and the precipitated crude product was filtered off with suction and dissolved again in ethyl acetate. After washing twice in each case with water, satd. bicarbonate solution and satd. common salt solution and drying the organic phase using sodium sulphate, after concentration to dryness 17(3-cyano-15R,1613-methylene -613-tosyloxymethyl -1 9-nor-androst-4-en-3-one was obtained, which was used further without purification.

8b.
17R-Cyano-6,6-ethylene-15(3,1613-methylene-l9-nor-androst-4-en-3-one 450 mg of sodium hydride were added at room temperature in portions to a solution of 3 g of trimethylsulphoxonium iodide in 50 ml of dry DMSO and, after addition was complete, the mixture was stirred at room temperature for 1 hour.
Subsequently, the solution of 1.5 g of 179-cyano-1513,1613-methylene -6f3-tosyloxymethyl-19-nor-androst-4-en-3-one was added to the ylide formed and the mixture was stirred at room temperature for 6 hours. After termination of the reaction by the addition of 350 ml of water, extraction twice with 150 ml of ethyl acetate, washing the organic phase with water and saturated common salt solution and drying over sodium BSP 53615A WO (engl) sulphate, the organic phase was concentrated, and 17(3-cyano-6,6-ethylene-15(3,16f3-methylene-19-nor-androst-4-en-3-one was obtained.

'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8= 0.39-1.02(m,6H,6,6-ethylene/cyclopropyl) 1.11(s,3H,18-CH3) 5.70(s,1 H, H-4) Example 9 17R-Cyano-6I3,7t3-methylene-15f3,16(3-methylene-19-nor-androst-4-en-3-one and 17f3-cyano-6a,7a-methylene-159,16(3-methylene-19-nor-androst-4-en-3-one 714 mg of sodium hydride (60% strength in paraffin) were added in portions at room temperature to a solution of 3.93 g of trimethylsulphoxonium iodide in 38 ml of dry dimethyl sulphoxide and, after addition was complete, the mixture was stirred at room temperature for 1 hour. Subsequently, the solution of 2.0 g of 17f3-cyano-15(3,16(3-methylene-l9-nor-androsta-4,6-dien-3-one in dimethyl sulphoxide was added to the ylide formed and the mixture was stirred at room temperature for 6 hours.
After termination of the reaction by addition of 150 ml of ammonium chloride solution, extraction twice with 75 ml of ethyl acetate, washing the organic phase with water and saturated common salt solution and drying over sodium sulphate, the organic phase was concentrated to dryness. After flash chromatography on silica gel using hexane/ethyl acetate and subsequent HPLC separation on a chiral stationary normal phase using an eluent of hexane and ethanol, 17f3-cyano-6f3,7(3-methy{ene-15f3,16f3-methylene-19-nor-androst-4-en-3-one was obtained as fraction I and 17R-cyano-6a,7a-methylene-15f3,16f3-methylene-l9-nor-androst-4-en-3-one was obtained as fraction II.

17(3-Cyano-69,7(3-methylene-1591 6f3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8= 0.46-0.62(2 x m,2H,cyclopropyl) 1.06(s,3H,18-CH3), 2.79(d,1 H,J=4.14, H-17), 6.12(s,1 H, H-4) 1 7f3-Cvano-6a, 7a-methylene-15f3 16f3-methylene-19-nor-androst-4-en-3-one:

= CA 02690959 2009-12-07 BSP 53615A WO (engi) 'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8= 0.49, 0.77, 0.83, 0.98(4 x m,4H,cyclopropyl) 1.11(s,3H,18-CH3), 2.77(d,1 H,J=4.40, H-17), 6.05(s,1 H, H-4) Example 10 179-Cyano-l7a-methyl-159,169-methylene-19-nor-androst-4-en-3-one 10a.
179-Cyano-17a-methyl-15(3,169-methylene 3-methoxy-19-nor-androsta-3,5-diene 14.7 ml of 2 M lithium diisopropylamide solution were added dropwise at -78 C
to a solution of 2.6 g of 1713-cyano-1513,16f3-methylene 3-methoxy-1 9-nor-androsta-3,5-diene in 80 ml of THF. The mixture was stirred at -78 C for 1 hour, 2.35 ml of methyl iodide were added and it was then warmed to room temperature. 25 ml of saturated ammonium chloride were added, and the mixture was extracted with three times 100 ml of ethyl acetate. The combined organic extracts were concentrated and crystallized from methanol. 17(3-Cyano-17a-methyl-1513,169-methylene 3-methoxy-19-nor-androsta-3,5-diene was obtained, which was immediately reacted further.
10b.
17(3-Cyano-17a-methyl-15R,16(3-methylene-19-nor-androst-4-en-3-one 2g of 179-cyano-17a-methyl-1513,1613-methyfene 3-methoxy-1 9-nor-androsta-3,5-diene were taken up in 50 ml of methanol, and treated with 3 ml of 1 N
hydrochloric acid. After 1 hour, the mixture was neutralized with saturated sodium hydrogencarbonate solution and concentrated in vacuo, the product precipitating out.
It was filtered off with suction, washed with water and recrystallized from ethyl acetate. 17f3-Cyano-17a-methyl-15R,169-methylene-19-nor-androst-4-en-3-one was obtained.

'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8 0.42(m, 1 H, cyclopropyl) 0.86 (m,1 H, cyclopropyl), 1.06 (m,1 H, cyclopropyl), 1.18(s,3H, 18-CH3 ), 1.37(s,3H, 17-CH3 ), 5.84(s,1H, H-4) BSP 53615A WO (engl) BSP 53615A WO (engl) Example 11 17 (3-Cyano-6(3-hydroxymethyl-l9-nor-a nd rost-4-en-3-one 17f3-Cyano-19-nor-androst-4-en-3-one was reacted analogously to the procedure indicated in Example 8. 17f3-Cyano-6f3-hydroxymethyl-19-nor-androst-4-en-3-one was obtained.

'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): b=
0.97(s,3H, 18-CH3), 3.66(m,2H,CH2OH) 5.91(s,1H, H-4) Example 12 17R-Cyano-6,6-ethylidene-19-nor-androst-4-en-3-one 17f3-Cyano-6f3-hydroxymethyl-19-nor-androst-4-en-3-one was reacted analogously to the procedures indicated in Examples 8a and 8b. 17R-Cyano-6,6-ethylidene-19-nor-androst-4-en-3-one was thus obtained.

'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8= 0.41 (m,1H), 0.54 (m,1H), 0.68 (m,1H), 1.01(s,3H,18-CH3), 2.45 (s broad,1H), 5.69 (s,1H, H-4) Example 13 17(3-Cyano-19-nor-androsta-4,6-di en-3-one 13a.
1713-Cyano-3-methoxy-19-nor-a ndrosta-3,5-diene 179-Cyano-19-nor-androst-4-en-3-one was reacted analogously to the method indicated in procedure 2a. 17f3-Cyano-3-methoxy-19-nor-androsta-3,5-diene was obtained.

1H-NMR (d6-DMSO): 0.81 (s,3H, 18-CH3 ), 3.45(s,3H,OCH3), 5.19(s broad,2H, H-4 and H-6) BSP 53615A WO (engi) 13b.
1713-Cyano-19-nor-androsta-4,6-dien-3-one 179-Cyano-3-methoxy-19-nor-androsta-3,5-diene was reacted analogously to the method indicated in procedure 2b. 17f3-Cyano-19-nor-androsta-4,6-dien-3-one was obtained.

'H-NMR(d6-DMSO): 0.86(s,3H, 18-CH3 ), 2.80(d,1H,J=4.4, H-17), 5.69(s,1H, H-4), 6.18(m,1H, H-6), 6.24(m,1H,H-7) Example 14 17R-Cyano-66, 7t3-methylene-l9-nor-androst-4-en-3-one and 179-cyano-6a, 7a-methylene-19-nor-androst-4-en-3-one 179-Cyano-19-nor-androsta-4,6-dien-3-one was reacted analogously to the method indicated in Example 9. 17f3-Cyano-69, 7R-methylene-19-nor-androst-4-en-3-one and 17(3-cyano-6a,7a-methylene-l9-nor-androst-4-en-3-one were obtained.
17f3-Cyano-6f3, 7(3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8= 0.52 (m,1 H), 0.97 (m,1 H), 0.97(s,3H,18-CH3), 6.11 (s,1 H, H-4) 1 7 (3-Cyano-6a, 7a-methylene-19-nor-and rost-4-en-3-one:
'H-NMR (300 MHz, CDC13 TMS as internal standard, selected signals): 8= 0.66 (m,1H), 0.78 (m,1H), 0.89 (m,1 H), 1.01(s,3H,18-CH3), 6.03 (s,1 H, H-4) Example 15 17t3-Cyano-7a-methyl-19-nor-androst-4-en-3-one and 17R-cyano-713-methyl-19-nor-androst-4-en-3-one 179-Cyano-19-nor-androsta-4,6-dien-3-one was reacted analogously to the method indicated in Example 3. 17f3-Cyano-7a-methyf-19-nor-androst-4-en-3-one and 17(3-cyano-7(3-methyl-19-nor-androst-4-en-3-one were obtained.

BSP 53615A WO (engl) 17(3-Cyano-7a-methyl-19-nor-and 9-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8= 0.77 (d,3H, 7-CH3, J=7Hz), 1 A0(s,3H,18-CH3), 5.84 (s, 1 H, H-4) 17 f3-C va no-7 f3-m eth yl-19-n or-a n d rost-4-en-3 -o n e:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8= 0.78 (d,3H, 7-CH3, J=7 Hz), 1.00(s,3H,18-CH3), 5.85 (s,1 H, H-4) Example 16 17(3-Cyano-7a-ethyl-19-nor-androst-4-en-3-one and 17(3-cyano-79-ethyl-19-nor-androst-4-en-3-one 179-Cyano-19-nor-androsta-4,6-dien-3-one was reacted analogously to the method indicated in Example 3, working with ethylmagnesium bromide in diethyl ether instead of with methylmagnesium bromide. 17f3-Cyano-7a-ethyf-19-nor-androst-4-en-3-one and 17f3-cyano-79-ethyl-19-nor-androst-4-en-3-one were obtained.

1 713-Cya n o-7 a-et h yl-19- no r-a n d rost-4-e n-3-o n e:
'H-NMR (d6-DMSO): 0.80 (t,3H, 7-CH2-CH3, J=7.5Hz), 0.87(s,3H,18-CH3), 5.73 (s,1 H, H-4) 17f3-Cvano-7f3-ethyl-19-nor-a nd rost-4-en-3-one:
1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): S= 0.88 (t,3H, 7-CH2-CH3, J=7.5Hz), 1.00(s,3H,18-CH3), 5.82 (s,1H, H-4) Example 17 17(3-Cyano-7a-vinyl-19-nor-androst-4-en-3-one and 17t3-cyano-7(3-vinyl-19-nor-androst-4en-3-one 179-Cyano-19-nor-androsta-4,6-dien-3-one was reacted analogously to the method indicated in Example 3, working with vinylmagnesium bromide instead of with methylmagnesium bromide. 17(3-Cyano-7a-vinyl-19-nor-androst-4-en-3-one and 17R-cyano-7f3-vinyl-19-nor-androst-4-en-3-one were obtained.

BSP 53615A WO (engi) 1 7 (3-Cyano-7a-vi ny1-19-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 6 0:99(s,3H, 18-CH3 ), 5.10(m,2H, CH2=CH), 5.70 (m,1 H,CH2=CH), 5.85 (s,1 H, H-4) 17R-Cyano-7f3-vinyl-19-nor-androst-4-en-3-one:
1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): S=
0.99(s,3H, 18-CH3), 4.94(d broad,1H,J=10Hz, CH2=CH), 5.04(d broad,1H,J=17Hz, CH2=CH), 5,71 (m,1H,CH2=CH), 5.84 (s,1H, H-4) Example 18 17R-Cyano-7a-cyclopropyl-19-nor-androst-4-en-3-one and 179-cyano-7R-cyclopropyl-19-nor-androst-4-en-3-one 17f3-Cyano-19-nor-androsta-4,6-dien-3-one was reacted analogously to the method indicated in Example 3, working with cyclopropylmagnesium bromide instead of with methylmagnesium bromide. 1713-Cyano-7a-cyclopropyl-19-nor-androst-4-en-3-one and 179-cyano-7f3-cyclopropyl-19-nor-androst-4-en-3-one were obtained.

17f3-Cya no-7a-cycl op ropyl- 1 9-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8 0.05(m,1H,cyclopropyl), 0.27(m,1H,cyclopropyl), 0.47(m,3H, cyclopropyl), 1.00(s,3H, 18-CH3 ), 5.88(s,1 H, H-4) 179-Cyano-79-cyclopropyl-19-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 6 0.13(m,1H,cyclopropyl), 0.29(m,1H,cyclopropyl), 0.58(m,4H, cyclopropyl), 1.01(s,3H, 18-CH3 ), 5.81(s,1 H, H-4) Example 19 17a-Allyl-17(3-cyano-l9-nor-an drost-4-e n-3-one 17(3-Cyano-3-methoxy-19-nor-androsta-3,5-diene was reacted analogously to the methods indicated in Examples 10a (allyl bromide being used instead of methyl iodide) and 10b. 17a-Allyl-1713-cyano-19-nor-androst-4-en-3-one was obtained.

BSP 53615A WO (engl) 'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 6 0.85(m,1H), 1.15(s,3H, 18-CH3 ), 5.22 (m,2H, -CH=CH2), 5.84(s,1H, H-4), 5.92 (m,1H, -CH=CH2) Example 20 17 R-Cyano-17a-ethyl-l9-nor-androst-4-e n-3-one 17f3-Cyano-3-methoxy-19-nor-androsta-3,5-diene was reacted analogously to the methods indicated in examples 10a (ethyl iodide being used instead of methyl iodide) and 10b. 17f3-Cyano-17a-ethyl-l9-nor-androst-4-en-3-one was obtained.

'H-NMR (d6-DMSO): 0.97(t,3H, 17-CH2-CH3), 1.00(s,3H, 18-CH3 ), 5.69 (m,1 H, -CH=CH2) Example 21 17 (3-Cyano-17a-methyl-19-nor-androst-4-en-3-one 21 a.
179-Cyano-l7a-methyl-3-methoxy-19-nor-androsta-3,5-diene 179-Cyano-3-methoxy-19-nor-androsta-3,5-diene was reacted analogously to the method indicated in example 10a. 17(3-Cyano-17a-methyl-3-methoxy-19-nor-androsta-3,5-diene was obtained.

'H-NMR (d6-DMSO): 0.93(s,3H), 1.20(s,3H), 3.45 (s.3H, 3-O-CH3), 5.19 (m,2H, H4 and H6) 21 b.
17 R-Cya no-l7a-methyl-19-nor-a nd rost-4-e n-3-on e 17(3-Cyano-17a-methyl-3-methoxy-19-nor-androsta-3,5-diene was reacted analogously to the method indicated in Example 10b. 17f3-Cyano-17a-methyl-19-nor-androst-4-en-3-one was obtained.

= CA 02690959 2009-12-07 BSP 53615A WO (engi) 'H-NMR (d6-DMSO): 0.97(s,3H), 1.19(s,3H), 5.69 (s,1H, H-4) Example 22 17t3-Cya no-6(3-hydroxymethyl-l7a-methyl-19-nor-a nd rost-4-en-3-one 17f3-Cyano-17a-methyl-19-nor-androst-4-en-3-one was reacted analogously to the procedure indicated in Example 8. 17R-Cyano-613-hydroxymethyl-l7a-methyl-19-nor-androst-4-en-3-one was obtained.

'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): &_ 1.09(s,3H), 1.29(s,3H), 3.68 (m,2H, 6-CH2-OH), 5.91(s,1H, H-4) Example 23 17f3-Cyano-6, 6-ethyl idene-17a-methyl-19-nor-androst-4-en-3-one 17f3-Cyano-6(3-hydroxymethyl-17a-methyl-19-nor-androst-4-en-3-one was reacted analogously to the procedures indicated in Examples 8a and 8b . 17f3-Cyano-6,6-ethylidene-17a-methyl-19-nor-androst-4-en-3-one was obtained.

1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): S=
0.40(m,1 H), 0.54(m,1 H), 0.68(m,1 H), 0.94(m,2H), 1.11(s,3H), 1.29(s,3H), 5.68(s,1 H, H-4) Example 24 179-Cyano-17a-methyl-19-nor-a ndrosta-4, 6-d ien-3-one 17f3-Cyano-3-methoxy-19-nor-androsta-3,5-diene was reacted analogously to the method indicated in Example 2b. 17I3-Cyano-17a-methyl-l9-nor-androsta-4,6-dien-one was obtained.

1 H-NMR(d6-DMSO): 1.04(s,3H), 1.25(s,3H), 5.73(s,1H, H-4), 6.23(m,1H, H-6), 6.29 (m,1 H, H-7) BSP 53615A WO (engi) Example 25 179-Cyano-7a,17a-bismethyl-l9-nor-androst-4-e n-3-one 17t5-Cyano-17a-methyl-19-nor-androsta-4,6-dien-3-one was reacted analogously to the method indicated in Example 3. 17R-Cyano-7a117a-bismethyl-19-nor-androst-4-en-3-one was obtained.

'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): S
0.78(d,3H,J=7Hz,7-CH3), 1.11(s,3H), 1.31 (s,3H), 5.84(s,IH, H-4) Example 26 179-Cyano-17a-methyl-7a-vinyl-19-nor-androst-4-en-3-one and 17t3-cyano-17a-methyl-79-vinyl-19-nor-androst-4-en-3-one 17(3-Cyano-17a-methyl-19-nor-androsta-4,6-dien-3-one was reacted analogously to the method indicated in Example 3, working with vinylmagnesium bromide instead of with methylmagnesium bromide. 17f3-Cyano-17a-methyl-7a-vinyl-19-nor-androst-4-en-3-one and 17(3-cyano-17a-methyl-7(3-vinyl-19-nor-androst-4-en-3-one were obtained.

17 f3-Cyano-17a-methyl-7a-vi 7a-methyl-7a-vinyl-1 9-nor-andr 'H-NMR (300 MHz, CDCl3 TMS as internal standard, selected signals): 8 1.11(s,3H), 1.24-1.31(m,8H), 5.10(m,2H,7-CH=CH2), 5.70(m,1H,7-CH=CH2), 5.89(s,1 H, H-4) 17f3-Cyano-17a-methyl-713-vinyl-l9-nor-androst-4-en-3-one:
1H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): S=
1.09(s,3H), 1.26(s,3H), 4.93(d broad,1H,J=10Hz, 7-CH=CH2), 5.03(d broad,l H,J=17Hz, 7-CH=CH2), 5.71(m,1 H,7-CH=CH2), 5.83(s,1 H, H-4) BSP 53615A WO (engl) Example 27 1713-Cyano-7a-cyclopropyl-17a-methyl-l9-nor-androst-4-en-3-one and 17(3-cyano-7(3-cyclopropyl-17a-methyl-19-nor-androst-4-en-3-one 17f3-Cyano-17a-methyl-19-nor-androsta-4,6-dien-3-one was reacted analogously to the method indicated in Example 3, working with cyclopropylmagnesium bromide instead of with methylmagnesium bromide. 17f3-Cyano-7a-cyclopropyl-17a-methyl-19-nor-androst-4-en-3-one and 1713-cyano-7R-cyclopropyl-l7a-methyl-19-nor-androst-4-en-3-one were obtained.

17f3-Cyano-7a-cyclopropyl-17a-methyl-19-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCI3 TMS as internal standard, selected signals): 8 _-0.05(m,1 H), 0.26(m,1H), 0.39-0.58(m,3H), 1.10(s,3H), 1.32(s,3H), 5.89(s,1 H, H-4) 17f3-Cyano-713-cyclopropyl-l7a-methyl-19-nor-androst-4-en-3-one:
'H-NMR (300 MHz, CDCf3 TMS as internal standard, selected signals): S=
0.12(m,1 H), 0.30(m,1 H), 0.59(m,4H), 0.87(m,1 H), 1.12(s,3H), 1.30(s,3H), 5.81(s,1 H, H-4) Example 28 179-Cyano-17a-methyl -15(3,16(3-methylene-19-nor-androsta-4,6-dien-3-one A suspension of 3.4 g of 17(3-cyano-17a-methyl-15f3,169-methylene 3-methoxy-19-nor-androsta-3,5-diene in 100 ml of 1-methyl-2-pyrrolidone was treated successively at 0 C with 4 ml of a 10% strength sodium acetate solution and at this temperature with 1.6 g of 1,3-dibromo-5,5-dimethylhydantoin in portions, stirred at 0 C
for 0.5 hour (ice bath), treated with 1.5 g of lithium bromide and 1.3 g of lithium carbonate, and stirred for 3.5 hours at a bath temperature of 100 C.
Subsequently, it was stirred into a mixture of ice water and common salt solution, the precipitate was filtered off and the filter cake was recrystallized from dimethoxyethane. 179-Cyano-17a-methyl -159,169-methylene-19-nor-androsta-4,6-dien-3-one was obtained.

BSP 53615A WO (engi) 17(1-Cyano-17a-methyl-15(3 16(3-methylene-19-nor-androsta-4, 6-dien-3-one:
'H-NMR (300 MHz, CDC13 as internal standard, selected signals): 8 = 0.55(m,1 H, cyclopropyl) 1. 18 (m,1 H, cyclopropyl), 1.25(s,3H, 18-CH3 ), 1.44(s,3H, 17-CH3 ), 5.85(s,1 H, H-4), 6.29(m,1 H, H-6), 6.45(m,1 H,H-7) Example 29 17R-Cyano-l7a-ethyl-159,16(3-methylene-l9-nor-androst-4-en-3-one 29a.
179-Cyano-17a-ethyt-159,169-methytene 3-methoxy-19-nor-androsta-3,5-diene 179-Cyano-159,169-methylene 3-methoxy-l9-nor-androsta-3,5-diene was reacted as described in Example 10a. Instead of the methyl iodide employed there, ethyl iodide was used here. 17f3-Cyano-17a-ethyl-15(3,16(3-methylene 3-methoxy-1 9-nor-androsta-3,5-diene was obtained.
29b.
179-Cyano-17a-ethyl-15R,16R-methylene-19-nor-androst-4-en-3-one The compound described in Example 19a was reacted analogousiy to the procedure indicated in Example 10b. 17(1-Cyano-17a-ethyl-15I3,16(3-methylene-19-nor-androst-4-en-3-one was obtained.

17f3-Cyano-17a-ethyl-1513,16(3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.46(m,1H, cyclopropyl) 0.87 (m,1H, cyclopropyl), 1.08 (m,1H, cyclopropyl), 1.21(m,7H, 18-CH3,17-CH2-CH3, cyclopropyl ), 5.86(s,1 H, H-4) Example 30 17t3-Cya no-17a-ethyl-6(3-hydroxym ethyl-15R,169-methylene-l9-nor-androst-4-en-3-one 17(3-Cyano-17a-ethyl-15(1,1613-methylene-19-nor-androst-4-en-3-one was reacted analogously to Example 7, and 17(3-cyano-17a-ethyl-613-hydroxymethyl-15(3,1613-methylene-19-nor-androst-4-en-3-one was obtained.

BSP 53615A WO (engl) 17 R-Cya no-17a-ethyl-6f3-hyd roxym ethyl-15f3 1613-methylene-19-nor-androst-4-en-3-one:
1H-NMR (CDCI3) : 0.46(m,1H,cyclopropyl), 1.19(m,6H, 17-CH2-CH3, 18-CH3), 3.74(m,2H,CH2OH) 5.94(s,1H, H-4) Example 31 179-Cyano-l7a-ethyl-6,6-ethylene-15R,169-methylene-l9-nor-androst-4en-3-one 1 7 f3-Cyano-17a-ethyl-6f3-hydroxymethyl-15f3,16f3-methylene-19-nor-androst-4-en-3-one was reacted analogously to Example 8, 17f3-cyano-17a-ethyl-6,6-ethylene-1513,16f3-methylene-19-nor-androst-4-en-3-one was obtained.
17f1-Cyano-17a-ethyl-6,6-ethylene-1513,16R-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.43(m,2H,6,6-ethylene/cyclopropyl), 0.59, 0.79, 0.96, 1.08(4 x m,4H,6,6-ethylene), 1.22(m,6H, 17-CH2-CH3, 18-CH3) 5.70(s,1 H, H-4) Example 32 17(3-Cyano-l7a-ethyl-15R,16(3-methylene-19-nor-androsta-4,6-dien-3-one From 179-cyano-17a-ethyl-15f3,16f3-methylene 3-methoxy-1 9-nor-androsta-3,5-diene, 179-cyano-17a-ethyl-1513,16f3-methylene-19-nor-androsta-4,6-dien-3-one was obtained analogously to the procedure indicated in Example 2b.
17f3-Cyano-17a-ethyl-159,16f3-methyl ene-19-nor-androsta-4, 6-dien-3-one:
'H-NMR (CDCI3) : 0.53(m,1H, cyclopropyl) 1.09-1,28 (m,9H, 18-CH3, 17-CH2-CH3 cyclopropyl), 5.80(s, 1 H, H-4), 6.25(m,1H, H-6), 6.40(m, 1 H, H-7) BSP 53615A WO (engi) Example 33 17 (3-Cya no-l7a-eth yl-7a-m ethyl-1513,16t3-m ethyl e ne-19-nor-a ndrost-4-e n-3-on e and 17(3-cyano-17a-ethyl-7(3-methyl 15t3,16t3-methylene-19-nor-androst-4-en-3-one 17R-Cyano-l7a-ethyl-1513,16f1-methylene-19-nor-androsta-4,6-dien-3-one was reacted analogously to Example 3, and after chromatography, 17(3-cyano-17a-ethyl-7a-methyl-15(3,16f3-methylene-19-nor-androst-4-en-3-one was obtained as fraction I
and 17f3-cyano-17a-ethyl-7f3-methyl 159,16R-methylene-19-nor-androst-4-en-3-one was obtained as fraction II.

1713-Cya no-17a-ethyl-7a-methyl-15(3,16f3-methylene-19-nor-androst-4-en-3-one:
1H-NMR (CDCI3) : 0.45(m,1H, cyclopropyl), 0.87(d,3H,J=7,34, T-CH3), 1.23 (m,6H, 18-CH3, 17-CH2-CH3 ), 5.86(s,1 H, H-4) 17f3-Cyano-17a-ethyl-7f3-methyl 15f3,1613-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.53(m,1H, cyclopropyl), 1.22 (m,9H, 7-CH3,18-CH3, 17-CH2-CH3 ), 5.82(s,1H, H-4) Example 34 17(3-Cyano-17a,7a-diethyl-15R,16R-methylene-l9-nor-androst-4-en-3-one and 1713-cyano-17a,7f3-diethyl-15t3,16R-methylene-l9-nor-androst-4-en-3-one According to the method of Example 3 using ethylmagnesium bromide in ether instead of methylmagnesium bromide, from 17f3-cyano-17a-ethyl-15f3,16f3-methylene-19-nor-androsta-4,6-dien-3-one, after chromatography, 1713-cyano-17a,7a-diethyl-15f3,16(3-methylene-19-nor-androst-4-en-3-one was obtained as fraction I and 17f3-cyano-17a,7f3-diethyl-15f3,16f3-methylene-19-nor-androst-4-en-3-one was obtained as fraction II.

17(3-Cyano-17a, 7a-di ethyl-15f3,16f3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.46 (m,1H,cyclopropyl) 0.92 (t,3H,J=7.34, 7-CH2-CH3), 1.23(m,6H, 18-CH3, 17-CH2-CH3 ), 5.87(s,1 H, H-4) BSP 53615A WO (engl) 17f3-Cyano-17a 7(3-diethyl-15f3 16f3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDC13) : 0.54 (m,1 H,cyclopropyl) 0.94 (t,3H,J=7.34, 7-CH2-CH3), 1.21(t,3H, J=7.34,17-CH2-CH3) 1.24(s,3H, 18-CH3 ), 5.84(s,1H, H-4) Example 35 17 R-Cyan o-17a-ethyl-7a-vi nyl-1513,16 R-methyle ne-19-nor-a n d rost-4-e n-3-on e and 17R-cyano-17a-ethyl-7(3-vinyl-15f3,16t3-methylene-l9-nor-androst-4-en-3-one According to the method of Example 3 using vinylmagnesium bromide instead of methylmagnesium bromide, from 17&cyano-17a-ethyl-15f3,16(3-methylene-19-nor-androsta-4,6-dien-3-one, after chromatography, 17f3-cyano-17a-ethyl-7a-vinyl-159,1613-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and 17f3-cyano-17a-ethyl-7(3-vinyl-1511,16f3-methylene-19-nor-androst-4-en-3-one is obtained as fraction II.

17f3-Cyano-17a-ethyl -7a-vinyf-15f1,169-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDC13) : 0.46 (m, 1 H,cyclopropyl), 1.08(m, 1 H,cyclopropyl) 1.22(m,3H, CH2-CH3 ),1.27(s,3H,18-CH3),5.17(m,2H, CH2=CH), 5.81 (m,1H,CH2=CH) 5.87(s,1H, H-4) 17(3-Cyano-17a-ethyl-7f3-vinyl-15fS,16f3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.42 (m, 1 H,cyclopropyl), 0.99(m, 1 H,cyclopropyl) 1.24(m,6H, 18-CH3, CH2-CH3),5.02(m,2H, CH2=CH), 5.85(s,1H, H-4), 5.90 (m, 1 H,CH2=CH) Example 36 17R-Cyano-l7a-ethyl-7a-cyclopropyl-15t3,16(3-methylene-l9-nor-androst-4-en-3-one and 17f3-cya no-l7a-ethyl-7R-cyclopropyl-15t3,1613-methylene-l9-nor-androst-4-en-3-one According to the method of Example 3 using cyclopropylmagnesium bromide instead of methylmagnesium bromide, from 17f3-cyano-17a-ethyl-15(3,16(3-methylene-19-nor-androsta-4,6-dien-3-one, after chromatography, 179-cyano-17a-ethyl-7a-cyclopropyl-15f3,16f3-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and BSP 53615A WO (engi) cyano-17a-ethyl-7f3-cyclopropyl-15R,16f3-methylene-19-nor-androst-4-en-3-one is obtained as fraction II.

17f3-Cyano-17a-ethyl-7a-cyclopropyl-15(3,16(3-methylene-19-nor-androst-4-en-3-one:
1 H-NMR (CDCI3) :-0.05(m,1 H,cyclopropyl), 0.26(m,1 H,cyclopropyl), 0.42(m,3H, cyclopropyl), 1.22(m,6H, CH2-CH3, 18-CH3 ), 5.90(s,1H, H-4) 1713-Cyano-17a-ethyl-7f3-cyclopropyl-15R,1613-methylene-l9-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.25(m, 1 H,cyclopropyl), 0.33(m, 1 H,cyclopropyl), 0.47(m,1 H,cyclopropyl), 0.60(m,2H, cyclopropyl), 1.06(m,1 H, cyclopropyl), 1.22(m,3H, CH2-CH3 ),1.27(s,3H, 18-CH3), 5.81(s,1H, H-4) Example 37 17(3-Cyano-l7a-ethyl-6R,7R-methylene-15(3,16R-methylene-l9-nor-androst-4-en-9-nor-androst-4-en-3-one and 17(3-cyano-l7a-ethyl-6a,7a-methylene-15(3,16R-methylene-l9-nor-androst-4-en-3-one 179-Cyano-17a-ethyl-15R,16f3-methylene-19-nor-androsta-4,6-dien-3-one is reacted according to the method indicated in Example 9 and, after chromatography, 1713-cyano-17a-ethyl-6f3,7f3-methylene-1513,16R-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and 17f3-cyano-17a-ethyl-6a,7a-methylene-15(3,16(3-methylene-19-nor-androst-4-en-3-one is obtained as fraction II.
179-Cvano-17a-ethyl-613, 713-methylene-15f3 169-methylene-19-nor-androst-4-en-one:
'H-NMR (CDCI3 ): 0.49(m, 1 H,cyclopropyl), 0.78(m,2H,cyclopropyl), 0.96(m,1 H,cyclopropyl), 1.13(m,1 H, cyclopropyl), 1.23(m,6H, CH2-CH3 ,18-CH3),6.05(s,1 H, H-4) 17R-Cyano-17a-ethyl-6a 7a-methylene-1513 16f3-methvlene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3 ): 0.52(m,1 H,cyclopropyl), 0.59(m,1 H,cyclopropyl), 0.97(m,1H,cyclopropyl), 1.17(m,1H, cyclopropyl), 1.18(s,3H,18-CH3),1.23(m,3H, CH2-CH3,),6.12(s,1H, H-4) BSP 53615A WO (engi) Example 38 178-Cyano-17a,7a-dimethyl-1513,169-methylene-19-nor-androst-4-en-3-one and 179-cyano-17a,7R-dimethyl 15f3,16R-methylene-19-nor-androst-4-en-3-one 17(3-Cyano-17a-methyl -15R,16(3-methylene-19-nor-androsta-4,6-dien-3-one is reacted analogously to Example 3, and, after chromatography, 17(3-cyano-17a,7a-dimethyl-159,16(3-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and 17f3-cyano-17a,713-dimethyl 1513,169-methylene-19-nor-androst-4-en-3-one is obtained as fraction II.

179-Cyano-17a,7a-dimethyl-159,16(3-methylene-19-nor-androst-4-en-3-one 'H-NMR (CDCI3) : 0.44 (m,1H,cyclopropyi) 0.85(d,3H,J=6.97Hz,7-CH3), 1.08(m,1 H,cyclopropyl)1.20(s,3H, 18-CH3 ), 1.40(s,3H, 17-CH3), 5.86(s,1 H, H-4) 17(3-Cyano-17a,7f3-dimethyl-15(3,169-methylene-19-nor-androst-4-en-3-one .
'H-NMR (CDCI3) : 0.51 (m,1 H,cyclopropyl), 0.98 (m,1 H,cyclopropyi), 1.06 (m,1 H,cyclopropyl), 1.20(s,3H, 18-CH3 ), 1.22 (d,3H,J=5.87Hz,7-CH3), 1.38(s,3H, 1 7-CH3 ), 5.83(s,1 H, H-4) Example 39 17(3-Cyano-17a-methyl-7a-ethyl-15R,16(3-methylene-l9-nor-androst-4-en-3-one and 17R-cyano-17a-methyl-7f3-ethyl-15R,16R-methylene-19-nor-androst-4-en-3-one 17(3-Cyano-l7a-methyl-1513,169-methylene-19-nor-androsta-4,6-dien-3-one is reacted according to the method of Example 3 using ethylmagnesium bromide in ether instead of methylmagnesium bromide, and, after chromatography, 17t3-cyano-17a-methyl-7a-ethyl-15f3,16f3-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and 17f3-cyano-17a-methyl-7f3-ethyl-159,16(3-methylene-19-nor-androst-4-en-3-one is obtained as fraction II.

17R-Cyano-17a-methyl -7a-ethyl-159,16f3-methylene-19-nor-androst-4-en-3-one:

BSP 53615A WO (engl) 'H-NMR (CDCI3) : 0.45 (m,1 H,cyclopropyl) 0.92 (m,3H, 7-CH3-CH2),1.20(s,3H, 18-CH3 ),1.39(s,3H, 1 7-CH3), 5.87(s,1 H, H-4) 1 7 f3-Cya no-17a-methyl-7f3-ethyl-15f3,16f3-methylene-l9-nor-and rost-4-en-3-one:
1H-NMR (CDCI3) : 0.52 (m,1H,cyclopropyl) 0.94 (m,3H, 7-CH2-CH3), 1.07(m, 1 H,cyclopropyl) 1.21 (s,3H, 18-CH3 ),1.38(s,3H,17-CH3), 5.84(s,1H, H-4) Example 40 179-Cyano-l7a-methyl-7a-vinyl-15(3,16(3-methylene-l9-nor-androst-4-en-3-one and 17(3-cyano-l7a-methyl-7f3-vinyl-15(3,16t3-methylene-l9-nor-androst-4-en-3-one 17i3-Cyano-17a-methy6-1513,169-methylere-'19-nor-ar ictrosta-4,6-d'rerr-3-one is reacted according to the method of Example 3 using vinylmagnesium bromide instead of methylmagnesium bromide, and, after chromatography, 17R-cyano-17a-methyl-7a-vinyl-15R,16(3-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and 17(3-cyano-17a-methyl-7f3-vinyl-15R,169-methylene-19-nor-androst-4-en-3-one is obtained as fraction II.

17(3-Cyano-17a-methyl -7a-vinyl-159,16(3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.45 (m,1 H,cyclopropyl), 1.09(m,1H,cyclopropyl)1.19(s,3H, 18-CH3 ), 1.37(s,3H, 17-CH3 ),5.16(m,2H, CH2=CH), 5.82 (m,1H,CH2=CH) 5.87(s,1H, H-4) 17(3-Cyano-17a-methvl -7f3-vinyl-15f3,169-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.40 (m,1H,cyclopropyl), 0.98(m,2H,cyclopropyl) 1.20(s,3H, 18-CH3 ), 1.36(s,3H, 17-CH3 ),5.03(m,2H, CH2=CH), 5.85(s,1H, H-4), 5.90 (m,1 H,CH2=CH) Example 41 179-Cyano-l7a-methyl-7a-cyclopropyl-15(3,16(3-methylene-l9-nor-androst-4-en-3-one and 17t3-cyano-17a-methyl-7t3-cyclopropyl-15R,16(3-methylene-19-nor-androst-4-en-3-one BSP 53615A WO (engi) 17(3-Cyano-17a-methyl-15R,16f3-methylene-19-nor-androsta-4,6-dien-3-one is reacted according to the method of Example 3 using cyclopropylmagnesium bromide instead of methylmagnesium bromide, and, after chromatography, 17f3-cyano-17a-methyl-7a-cyclopropyl-1513,1613-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and 17(3-cyano-17a-methyl-713-cyclopropyl-1513,16f3-methylene-19-nor-androst-4-en-3-one is obtained as fraction II.
17f3-Cyano-17a-methyl-7a-cyclopropyl-1513,1613-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.05(m,1 H,cyclopropyl), 0.35(m,1 H,cyclopropyl), 0.41(m,1H,cyclopropyl), 0.49(m,1H,cyclopropyl), 0.59(m,2H, cyclopropyl), 1.19(s,3H, 18-CH3 ), 1.41(s,3H, 17-CH3 ), 5.90(s,1H, H-4) 17f3-Cyano-17a-methyl-7f3-cyclopropyl-1513 16f3-methylene-19-nor-androst-4-en-one:
'H-NMR (CDCI3) : 0.25(m,1 H,cyclopropyl), 0.33(m,1 H,cyclopropyl), 0.45(m,1 H,cyclopropyl), 0.60(m,2H, cyclopropyl), 0.79(m,1 H,cyclopropyl), 0.87(m,1 H, cyclopropyl), 0.94(m,1 H, cyclopropyl), 1.07(m,1 H, cyclopropyl), 1.22(s,3H, 18-CH3), 1.39(s,3H, 17-CH3), 5.82(s,1H, H-4) Example 42 17(3-Cyano-l7a-methyl-6R-hydroxymethyl-15R,16(3-methylene-19-nor-androst-4-en-3-one 17f3-Cyano-17a-methyl-159,1613-methylene-19-nor-androst-4-en-3-one is reacted analogously to the process indicated in Example 7. 17(3-Cyano-17a-methyl-6f3-hydroxymethyl-15(3,169-methylene-19-nor-androst-4-en-3-one is obtained.

1 7 f3-Cyano-17a-methyl-6f3-hyd roxym ethyl-15(3 16f3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.45(m,1H,cyclopropyl), 1.08(m,1H,cyclopropyl), 1.18(s,3H, 18-CH3), 1.38(s,3H, 17-CH3),3.74(m,2H,CH2OH) 5.94(s, 1 H, H-4) BSP 53615A WO (engl) Example 43 17R-Cyano-l7a-methyl-6,6-ethylene-15t3,16(3-methylene-l9-nor-androst-4-en-3-one 1713-Cyano-17a-methyl-6(3-hydroxymethyl-15f3,1613-methylene-19-nor-androst-4-en-3-one is reacted analogously to the process indicated in Examples 8a and 8b.

Cyano-17a-methyl-6,6-ethylene-1513,1613-methylene-19-nor-androst-4-en-3-one is obtained.

17R-Cyano-1 7a-methyl-66-ethylene-1513 16f3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3) : 0.42-1.08(m,6H,6,6-ethylene/cyclopropyl)1.22(s,3H,18-CH3), 1.39(s,3H,17-CH3), 5.70(s,1 H, H-4) Example 44 17R-Cyano-17a-methyl-613,7t3-methylene-15(3,16(3-methylene-l9-nor-a nd rost-4-en-3-one and 17R-cyano-l7a-methyl-6a,7a-methytene-15R,1613-methylene-19-nor-androst-4-en-3-one 17f3-Cyano-17a-methyl-15f3,16f3-methylene-19-nor-androsta-4,6-dien-3-one is reacted analogously to the method indicated in Example 9 and 17(3-cyano-1 7a-methyl-6(3,7(3-methylene-15(3,1613-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and 179-cyano-1 7a-methyl-6a,7a-methylene-15f3,16f3-methylene-1 nor-androst-4-en-3-one is obtained as fraction IL

1713-Cyano-17a-methyl-613, 713-methylene-159,16(3-methylene-19-nor-androst-4-en-3-one:
'H-NMR (CDCI3): 0.47(m,1 H,cyclopropyl), 0.80(m,2H,cyclopropyl), 0.97(m,1H,cyclopropyl), 1.13(m,1H, cycfopropyl),1.22(s,3H, 18-CH3), 1.40(s,3H, CH3), 6.05(s,1H, H-4) 17R-Cyano-17a-methyl -6a,7a-methylene-1513,16f3-methylene-l9-nor-androst-4-en-3-one:
'H-NMR (CDCI3 ): 0.50(m,1H,cyclopropyl), 0.59(m,1H,cyclopropyl), 0.98(m,1 H,cyclopropyl), 1.16(s,3H, 18-CH3), 1.41(s,3H, 17-CH3), 6.12(s,1 H, H-4) BSP 53615A WO (engi) Example 45 17(3-Cyano-17a-methyl-6(3,7R-methylene-19-nor-androst-4-en-3-one and 17(i-cyano-17a-methyl-6a,7a-methylene-l9-nor-androst-4-en-3-one 17f3-Cyano-17a-methyl-19-nor-androsta-4,6-dien-3-one is reacted according to the method indicated in Example 9 and, after chromatography, 179-cyano-l7a-methyl-6a,7a-methylene-19-nor-androst-4-en-3-one is obtained as fraction I and 17(3-cyano-17a-methyl-6(3,7R-methylene-19-nor-androst-4-en-3-one is obtained as fraction II.
17f3-Cyano-l7a-methyl-6a,7a-methylene-19-nor-androst-4-en-3-one:
1H-NMR (CDCI3): 0.68 (m, 1 H), 0.77 (m, 1 H), 0.90 (m, 1 H), 1.12 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.68 (m, 1 H), 2.02 (m, 1 H), 2.17 (m, 1 H), 2.40 (m, 1 H), 2.51 (m, 1 H), 6.03 (s, 1 H, H-4) 17f3-Cyano-17a-methyl-6(3, 713-methylene-l9-nor-androst-4-en-3-one:
1H-NMR (CDC13): 0.52 (m, 1 H), 0.93 (m, 1 H), 1.08 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.95 (m, 1 H), 2.37-2.48 (m, 2H), 6.11 (s, 1 H, H-4) Example 46 4-C hl oro-17t3-cya no-l7a-ethyl-19-nor-androst-4-en-3-one 100 mg of 17f3-cyano-17a-ethyl-19-nor-androst-4-en-3-one are dissolved in 1.1 ml of pyridine and cooled to 0 C. After addition of 42 NI of sulfuryl chloride, the mixture is subsequently stirred at 0 C for 1.5 hours.
After admixing with saturated aqueous sodium bicarbonate solution, water and ethyl acetate, the phases are separated and the organic phase is washed with water and saturated aqueous sodium chloride solution. After drying of the organic phase over sodium sulfate and filtration, the filtrate is concentrated and the residue is chromatographed on silica gel using a mixture of ethyl acetate and n-hexane to obtain 4-chloro-17R-cyano-17a-ethyl-19-nor-androst-4-en-3-one.
4-Chloro-17(3-cyano-17a-ethyl-19-nor-androst-4-en-3-one:
'H-NMR (d6-DMSO): 0.97 (t, 3H, J=7.3, -CH2-CH3), 1.00 (s, 3H, -CH3), 1.99 (m, 1 H), 2.08-2.22 (m, 2H), 3.10 (m, 1 H) BSP 53615A WO (engi) Example 47 17(3-Cyano-3-hydroxyimino-17a-ethyl-l9-nor-androst-4-en-3-one 100 mg of 17f3-cyano-17a-ethyl-19-nor-androst-4-en-3-one are dissolved in 1 ml of pyridine and admixed with 34.5 mg of hydroxylamine hydrochloride. After one hour's stirring at 125 C bath temperature, the batch is partitioned between water and ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is concentrated. After chromatography on silica gel using a mixture of ethyl acetate and n-hexane, the product-containing eluate is concentrated and recrystallized from a mixture of acetone and diisopropyl ether to obtain 17(3-cyano-3-hydroxyimino-17a-ethyl-19-nor-androst-4-en-3-one as E/Z mixture of the oximmes.

1 7(3-Cyano-3-hydroxyim ino-17a-ethyl-l9-nor-and rost-4-en-3-one:
'H-NMR (d6-DMSO): 0.41 (m, 1 H), 0.96 (t, 3H, J-7.3, -CH2-CH3), 0.99 (s, 3H, -CH3), 2.82 and 2.98 (each m, together 1 H), 5.76 and 6.36 (each s, together I H, H-4) Example 48 17t3-Cyano-19-nor-androsta-4, 9-di en-3-o ne 48a 17(3-Cyano-3,3-dimethoxyestr-5(10)-ene 75 g of 3,3-dimethoxyestr-5(10)-en-17-one are reacted analogously to the method indicated in Example 1d. The crude product thus obtained is taken up in a mixture of diisopropyl ether and hexane, the residue is filtered off and the filtrate is concentrated. The evaporation residue is crystallized from diisopropyl ether to obtain 17f3-cyano-3, 3-dimethoxyestr-5(10 )-ene.

1713-Cya no-3, 3-di methoxyestr-5(10)-ene:
1H-NMR (d6-DMSO): 0.84 (s, 3H, 17-CH3), 1.46 (m, 1 H), 1.70 (m, 1 H), 2.57 (m, 1 H), 3.07 (s, 3H, 3-OCH3), 3.10 (s, 3H, 3-OCH3) BSP 53615A WO (engl) {
48b 17 f3-Cya n oestr-5 (10 )-e n-3-o n e 3 g of 179-cyano-3,3-dimethoxyestr-5(10)-ene are suspended in a mixture of 24 mi of dichloromethane and 70 ml of t-butanol. After addition of 28 mi of water and 0.11 mi of 60% perchloric acid, the batch is stirred until fully reacted, admixed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered and the filtrate is evaporated to dryness to leave 17(3-cyanoestr-5(10)-en-3-one which is further processed without purification.

48c 17 (3-Cyano-l9-nor-androsta-4,9-dier4-3-one 2.4 g of 1713-cyanoestr-5(10)-en-3-one are admixed with 35 mi of pyridine and 3.2 g of pyridinium hydrobromide-perbromide. The mixture is stirred at room temperature for 1 hour and then at 50 C for 4 hours. After cooling, 40 mi of ice-cold 6N
aqueous hydrochloric acid are added and the mixture is extracted with ethyl acetate.
The organic phase is washed with 1 N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and filtered, and the filtrate evaporation residue is purified by means of chromatography on silica gel using a mixture of ethyl acetate and n-hexane to obtain 17f3-cyano-19-nor-androsta-4,9-dien-3-one.

179-Cyano-19-nor-and rosta-4.9-dien-3-one:
1H-NMR (d6-DMSO): 0.94 (s, 3H, 17-CH3), 1.09-1.22 (m, 2H), 1.25-1.41 (m, 2H), 1.69 (m, 1 H), 2.59 (m, 1 H), 2.75-2.90 (m, 2H), 5.56 (s, 1 H, H-4)

Claims

1. 17.beta.-Cyano-19-nor-androst-4-ene derivative having the general chemical formula 1 where Z is selected from the group comprising O, two hydrogen atoms, NOR
and NNHSO2R, in which R is hydrogen or C1-C4-alkyl, R4 is hydrogen or halogen, furthermore either:
R6a, R6b together form methylene or 1,2-ethanediyl or R6a is hydrogen and R6b is selected from the group comprising hydrogen, methyl and hydroxymethylene, and R7 is selected from the group comprising hydrogen, C1-C4-alkyl, C2-C3-alkenyl and cyclopropyl, or:
R6a is hydrogen and R6b and R7 together form methylene or are omitted with formation of a double bond between C6 and C7 R9, R10 are hydrogen or are omitted with formation of a double bond between C9 and C10 R15, R16 are hydrogen or together form methylene, R17 is selected from the group comprising hydrogen, C1-C4-alkyl and allyl, where at least one of the substituents R4, R6a, R6b, R7, R15, R16 and R17 is unequal to hydrogen or R6b and R7 are omitted with formation of a double bond between C6 and C7, and its solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.

2. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to Claim 1, characterized in that R15 and R16 together form methylene.

3. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to one of the above claims, characterized in that Z is selected from the group comprising O, NOH
and NNHSO2H.

4. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to one of the above claims, characterized in that Z represents O.

5. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to one of the above claims, characterized in that R4 is hydrogen or chlorine.

6. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to one of the above claims, characterized in that R6a, R6b together form 1,2-ethanediyl or are in each case hydrogen.

7. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to one of the above claims, characterized in that R7 is selected from the group comprising hydrogen and methyl.

8. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to one of Claims 1 to 6, characterized in that R6b and R7 together form methylene.

9. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to one of the above claims, characterized in that R17 is selected from the group comprising hydrogen and methyl.

10. 17.beta.-Cyano-19-nor-androst-4-ene derivative according to Claim 1, selected from the group comprising 17.beta.-cyano-6.beta.-hydroxymethylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-19-nor-androst-4-en-3-one, 17.alpha.-Allyl-17.beta.-cyano-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-6,6-ethanediyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-6.beta.,7.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-6.alpha.,7.alpha.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-6.beta.-hydroxymethylene-19-nor-and 9-nor-androst-4-en-3-one, 17.beta.-cyano-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-6,6-ethanediyl-17.alpha.-methyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.alpha.-ethyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-6.alpha.,7.alpha.-methylene-19-nor-androst-4-en-3-one 17.beta.-cyano-17.alpha.-methyl-6.beta.,7.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.beta.-ethyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-19-nor-androsta-4,6-dien-3-one, 17.beta.-cyano-17.alpha.-methyl-19-nor-androsta-4,6-dien-3-one, 17.beta.-cyano-17.alpha.-methyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 7.alpha.,17.alpha.-bismethyl-17.beta.-cyano-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.alpha.-methyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.beta.-methyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.alpha.-vinyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.beta.-vinyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.alpha.-cyclopropyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.beta.-cyclopropyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.alpha.-cyclopropyl-17.alpha.-methyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.beta.-cyclopropyl-17.alpha.-methyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-7.alpha.-vinyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-7.beta.-vinyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-15.beta.,16.beta.-methylene-19-nor-androsta-4,6-dien-3-one, 17.beta.-cyano-15.beta.,16.beta.-methylene-6.beta.-hydroxymethylene-19-nor-androst-4-en-3-one, 17.alpha.-ethyl-17.beta.-cyano-15.beta.,16.beta.-methylene-6.beta.-hydroxymethyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-6.beta.,7.beta.-15.beta.,16.beta.-bismethylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-6.alpha.,7.alpha.-15.beta.,16.beta.-bismethylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.beta.-cyclopropyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.alpha.-cyclopropyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.beta.-ethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.alpha.-ethyl-15.beta.,16.beta.-methylene-19-nor-androst-4--en-3-one, 17.beta.cyano-7.beta.-methyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-7.alpha.-methyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-15.beta.,16.beta.-methylene-19-nor-androsta-4,6-dien-3-one, 17.beta.-cyano-17.alpha.-ethyl-15.beta.,16.beta.-methylene-19-nor-androsta-4,6-dien-3-one, 17.beta.-cyano-15.beta.,16.beta.-methylene-7.beta.-vinyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-15.beta.,16.beta.-methylene-7.alpha.-vinyl-19-nor-androst-4-en-3-one, 17.beta.-cyano-6,6-ethanediyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-15.alpha.,16.alpha.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.,7.alpha.-dimethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.,7.alpha.-dimethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.,7.beta.-dimethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-7.alpha.-ethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl 7.beta.-ethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl -7.alpha.-vinyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl -7.beta.-vinyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-7.alpha.-cyclopropyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-7.beta.-cyclopropyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-6.beta.-hydroxymethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-6,6-ethylene-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-6.beta.,7.beta.-methylene-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-methyl-6.alpha.,7.alpha.-methylene-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-7.alpha.-methyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-7.beta.-methyl 15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.,7.alpha.-diethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.,7.beta.-diethyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl -7.alpha.-vinyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-7.beta.-vinyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-7.alpha.-cyclopropyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-7.beta.-cyclopropyl-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-6,6-ethylene-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-6.beta.,7.beta.-methylene-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one, 17.beta.-cyano-17.alpha.-ethyl-6.alpha.,7.alpha.-methylene-15.beta.,16.beta.-methylene-19-nor-androst-4-en-3-one,

11. Use of the 17.beta.-cyano-19-nor-androst-4-ene derivative according to one of Claims 1 to 10 for the production of a medicament for oral contraception and for the treatment of pre-, peri- and postmenopausal symptoms.

12. Use according to Claim 11, characterized in that the medicament has gestagenic and antimineralcorticoid action.

13. Medicament comprising at least one 17.beta.-cyano-19-nor-androst-4-ene derivative according to one of Claims 1 to 10 and at least one suitable pharmaceutically harmless additive.

14. Medicament according to Claim 13, moreover comprising at least one oestrogen.

15. Medicament according to Claim 14, characterized in that the oestrogen is ethinylestradiol.

16. Medicament according to Claim 14, characterized in that the oestrogen is a natural oestrogen.

17. Medicament according to Claim 16, characterized in that the natural oestrogen is oestradiol.

18. Medicament according to Claim 16, characterized in that the natural oestrogen is oestradiol valerate.

19. Medicament according to Claim 16, characterized in that the natural oestrogen is a conjugated oestrogen.